CA1131224A - Process for the preparation of 1,2,3-thiadiazol-5-yl ureas - Google Patents
Process for the preparation of 1,2,3-thiadiazol-5-yl ureasInfo
- Publication number
- CA1131224A CA1131224A CA335,363A CA335363A CA1131224A CA 1131224 A CA1131224 A CA 1131224A CA 335363 A CA335363 A CA 335363A CA 1131224 A CA1131224 A CA 1131224A
- Authority
- CA
- Canada
- Prior art keywords
- compound
- general formula
- formula
- phenyl
- thiadiazole
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Expired
Links
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D285/00—Heterocyclic compounds containing rings having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by groups C07D275/00 - C07D283/00
- C07D285/01—Five-membered rings
- C07D285/02—Thiadiazoles; Hydrogenated thiadiazoles
- C07D285/04—Thiadiazoles; Hydrogenated thiadiazoles not condensed with other rings
- C07D285/06—1,2,3-Thiadiazoles; Hydrogenated 1,2,3-thiadiazoles
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Nitrogen- Or Sulfur-Containing Heterocyclic Ring Compounds With Rings Of Six Or More Members (AREA)
- Plural Heterocyclic Compounds (AREA)
Abstract
ABSTRACT OF THE DISCLOSURE
The invention provides a process for the preparation of 1, 2, 3-thiadiazol-5-yl ureas of the general formula I
wherein R1 represents a hydrogen atom, or an alkyl radical having 1 to 4 carbon atoms, and R2 respresents a (C1-C4)-alkyl, (C5-C8)-cycloalkyl, methyl-(C5-C8)-cycloalkyl, phenyl, halo-phenyl, (C1-C4)-alkylphenyl, (C1-C4)-alkoxyphenyl, nitrophenyl, trifluoromethylphenyl, pyridyl or pyrimidyl radical, which comprises reacting a compound of the formula II
with a compound III
in an inert organic solvent. Preferably tha compound II is formed in tbe reaction mixture. The process of the invent-ion makes it possible to prepare the ureas in a safe and tech-nically simple manner in virtually quantitative yields and good purity Previously the preparations required the use of 5-amino-1,2,3-thiadiazole which is not easily obtained and is not completely harmless.
The invention provides a process for the preparation of 1, 2, 3-thiadiazol-5-yl ureas of the general formula I
wherein R1 represents a hydrogen atom, or an alkyl radical having 1 to 4 carbon atoms, and R2 respresents a (C1-C4)-alkyl, (C5-C8)-cycloalkyl, methyl-(C5-C8)-cycloalkyl, phenyl, halo-phenyl, (C1-C4)-alkylphenyl, (C1-C4)-alkoxyphenyl, nitrophenyl, trifluoromethylphenyl, pyridyl or pyrimidyl radical, which comprises reacting a compound of the formula II
with a compound III
in an inert organic solvent. Preferably tha compound II is formed in tbe reaction mixture. The process of the invent-ion makes it possible to prepare the ureas in a safe and tech-nically simple manner in virtually quantitative yields and good purity Previously the preparations required the use of 5-amino-1,2,3-thiadiazole which is not easily obtained and is not completely harmless.
Description
" ~3~2~ ~
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~
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.
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).
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~
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.
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).
Claims (12)
PROPERTY OR PRIVILEGE IS CLAIMED ARE DEFINED AS FOLLOWS:
1. A process for the preparation of a compound of the general formula I
in which R1 represents a hydrogen atom, or an alkyl radical having 1 to 4 carbon atoms, and R2 represents a (C1-C4)-alkyl, (C5-C8)-cycloalkyl, methyl-(C5-C8)-cycloalkyl, phenyl, halo-phenyl, (C1-C4)-alkylphenyl, (C1-C4)-alkoxyphenyl, nitrophenyl, trifluoromethylphenyl, pyridyl or pyrimidyl radical, which comprises reacting a compound of the formula II
with a compound of the general formula III
wherein R1 and R2 have the meanings given above, in an inert organic solvent.
in which R1 represents a hydrogen atom, or an alkyl radical having 1 to 4 carbon atoms, and R2 represents a (C1-C4)-alkyl, (C5-C8)-cycloalkyl, methyl-(C5-C8)-cycloalkyl, phenyl, halo-phenyl, (C1-C4)-alkylphenyl, (C1-C4)-alkoxyphenyl, nitrophenyl, trifluoromethylphenyl, pyridyl or pyrimidyl radical, which comprises reacting a compound of the formula II
with a compound of the general formula III
wherein R1 and R2 have the meanings given above, in an inert organic solvent.
2. A process as claimed in claim 1, wherein the reaction is carried out at a temperature in the range of from 20 to 180°C
3. A process as claimed in claim 2, wherein the react-ion is carried out at a temperature in the range of from 50 to 120°C.
4. A process as claimed in claim 1, wherein the react-ion is carried out at the boiling temperature of the reaction mixture.
5. A process as claimed in claim 1, 2 or 3, wherein substantially equimolar amounts of the compound of the formula II
and the compound of the general formula III are reacted.
and the compound of the general formula III are reacted.
6. A process as claimed in claim 1, 2 or 3, where the reaction of the compound of the formula II with the compound of the general formula III is effected in one step.
7. A process as claimed in claim 1, 2 or 3, wherein the reaction of the compound of the formula II with the com-pound of the general formula III is carried out in a hydro-carbon, an ether, an ester, ketone, halogenated hydrocarbon or carboxylic acid nitrile.
8. A process as claimed in claim 1, wherein the com-pound of the formula II is prepared in situ, a) by reacting a compound of the formula IV
with a compound of the general formula Cl - CO - OR3 V
in an inert solvent in the presence of an acid-binding agent to form a compound of the general formula VI
and then reacting this with an aqueous solution of a compound of the general formula or b) by racting a compound of the general formula VIII
in an inert organic solvent with an aqueous solution of a com-pound of the general formula or c) by reacting a compound of the formula IX
in an inert solvent with an aqueous solution of a compound of the general formula or with an alkyl nitrite of the general formula in the presence of acid, to form a compound of the formula II
wherein R3 represents a (C1-C6)-alkyl radical, M denotes an alkali metal and X denotes a halogen atom.
with a compound of the general formula Cl - CO - OR3 V
in an inert solvent in the presence of an acid-binding agent to form a compound of the general formula VI
and then reacting this with an aqueous solution of a compound of the general formula or b) by racting a compound of the general formula VIII
in an inert organic solvent with an aqueous solution of a com-pound of the general formula or c) by reacting a compound of the formula IX
in an inert solvent with an aqueous solution of a compound of the general formula or with an alkyl nitrite of the general formula in the presence of acid, to form a compound of the formula II
wherein R3 represents a (C1-C6)-alkyl radical, M denotes an alkali metal and X denotes a halogen atom.
9. A process as claimed in claim 8, wherein R3 repre-sents a sodium, potassium or lithium atom.
10. A process as claimed in claim 8 or 9, wherein X
represents a chlorine atom.
represents a chlorine atom.
11. A process as claimed in claim 1, 2 or 3, wherein in the reactants R1 is hydrogen and R2 is phenyl.
12. A process as claimed in claim 1 which comprises reacting 1,2,3-thiadiazole-5-carboxylic acid azide with aniline in toluene.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| DEP2841825.9 | 1978-09-22 | ||
| DE19782841825 DE2841825A1 (en) | 1978-09-22 | 1978-09-22 | METHOD FOR THE PRODUCTION OF 1,2,3-THIADIAZOL-5-YL UREA |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA1131224A true CA1131224A (en) | 1982-09-07 |
Family
ID=6050477
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA335,363A Expired CA1131224A (en) | 1978-09-22 | 1979-09-11 | Process for the preparation of 1,2,3-thiadiazol-5-yl ureas |
Country Status (35)
| Country | Link |
|---|---|
| JP (1) | JPS5545683A (en) |
| AR (1) | AR223349A1 (en) |
| AT (1) | AT373593B (en) |
| AU (1) | AU533137B2 (en) |
| BE (1) | BE878925A (en) |
| BG (1) | BG30930A3 (en) |
| BR (1) | BR7905614A (en) |
| CA (1) | CA1131224A (en) |
| CH (1) | CH641792A5 (en) |
| CS (1) | CS209936B2 (en) |
| DD (1) | DD146184A5 (en) |
| DE (1) | DE2841825A1 (en) |
| DK (1) | DK361579A (en) |
| EG (1) | EG14167A (en) |
| ES (1) | ES483788A1 (en) |
| FI (1) | FI69838C (en) |
| FR (1) | FR2436783A1 (en) |
| GB (1) | GB2031889B (en) |
| GR (1) | GR73092B (en) |
| HU (1) | HU182999B (en) |
| IE (1) | IE48944B1 (en) |
| IL (1) | IL58274A (en) |
| IT (1) | IT1123731B (en) |
| LU (1) | LU81704A1 (en) |
| NL (1) | NL7905355A (en) |
| NZ (1) | NZ191603A (en) |
| PH (1) | PH15388A (en) |
| PL (1) | PL123956B1 (en) |
| PT (1) | PT70178A (en) |
| RO (1) | RO77754A (en) |
| SE (1) | SE435376B (en) |
| SU (1) | SU921466A3 (en) |
| TR (1) | TR20895A (en) |
| YU (1) | YU40759B (en) |
| ZA (1) | ZA794722B (en) |
Families Citing this family (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| DE2909991A1 (en) * | 1979-03-12 | 1980-10-02 | Schering Ag | 1,2,3-THIADIAZOL-5-CARBONIC ACID DERIVATIVES, METHOD FOR THE PRODUCTION OF THESE COMPOUNDS, AND THEIR CONTAINING AGENTS WITH HERBICIDAL AND GROWTH REGULATORY AND FUNGICIDAL EFFECT |
| JPS55150238U (en) * | 1980-04-03 | 1980-10-29 | ||
| DE3139506A1 (en) * | 1981-10-01 | 1983-04-21 | Schering Ag, 1000 Berlin Und 4619 Bergkamen | 1,2,3-THIADIAZOL-5-YL-UREA DERIVATIVES, METHOD FOR THE PRODUCTION OF THESE COMPOUNDS AND THEIR CONTAINING AGENTS WITH GROWTH REGULATIVE AND DEFOLIATING EFFECT |
Family Cites Families (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| DD103124A5 (en) | 1972-03-23 | 1974-01-12 | ||
| DE2636994C2 (en) | 1976-08-13 | 1984-10-18 | Schering AG, 1000 Berlin und 4709 Bergkamen | Process for the preparation of 5-amino-1,2,3-thiadiazole |
-
1978
- 1978-09-22 DE DE19782841825 patent/DE2841825A1/en not_active Withdrawn
-
1979
- 1979-07-09 NL NL7905355A patent/NL7905355A/en not_active Application Discontinuation
- 1979-08-20 YU YU2027/79A patent/YU40759B/en unknown
- 1979-08-29 DK DK361579A patent/DK361579A/en not_active Application Discontinuation
- 1979-08-31 BR BR7905614A patent/BR7905614A/en unknown
- 1979-08-31 ES ES483788A patent/ES483788A1/en not_active Expired
- 1979-09-06 FI FI792770A patent/FI69838C/en not_active IP Right Cessation
- 1979-09-06 ZA ZA00794722A patent/ZA794722B/en unknown
- 1979-09-11 CA CA335,363A patent/CA1131224A/en not_active Expired
- 1979-09-14 BG BG7944862A patent/BG30930A3/en unknown
- 1979-09-14 PT PT70178A patent/PT70178A/en unknown
- 1979-09-17 TR TR20895A patent/TR20895A/en unknown
- 1979-09-18 EG EG555/79A patent/EG14167A/en active
- 1979-09-18 NZ NZ191603A patent/NZ191603A/en unknown
- 1979-09-19 DD DD215645A patent/DD146184A5/en unknown
- 1979-09-19 IL IL58274A patent/IL58274A/en unknown
- 1979-09-20 CH CH850479A patent/CH641792A5/en not_active IP Right Cessation
- 1979-09-20 IT IT25880/79A patent/IT1123731B/en active
- 1979-09-20 SU SU792811707A patent/SU921466A3/en active
- 1979-09-20 GR GR60083A patent/GR73092B/el unknown
- 1979-09-20 PL PL1979218429A patent/PL123956B1/en unknown
- 1979-09-20 LU LU81704A patent/LU81704A1/en unknown
- 1979-09-20 PH PH23049A patent/PH15388A/en unknown
- 1979-09-21 IE IE1789/79A patent/IE48944B1/en unknown
- 1979-09-21 BE BE0/197257A patent/BE878925A/en not_active IP Right Cessation
- 1979-09-21 CS CS796380A patent/CS209936B2/en unknown
- 1979-09-21 AR AR278157A patent/AR223349A1/en active
- 1979-09-21 SE SE7907841A patent/SE435376B/en not_active IP Right Cessation
- 1979-09-21 AU AU51075/79A patent/AU533137B2/en not_active Ceased
- 1979-09-21 JP JP12093079A patent/JPS5545683A/en active Pending
- 1979-09-21 HU HU79SCHE691A patent/HU182999B/en unknown
- 1979-09-21 AT AT0622779A patent/AT373593B/en not_active IP Right Cessation
- 1979-09-21 GB GB7932815A patent/GB2031889B/en not_active Expired
- 1979-09-21 RO RO7998731A patent/RO77754A/en unknown
- 1979-09-24 FR FR7923681A patent/FR2436783A1/en active Granted
Also Published As
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CA1131224A (en) | Process for the preparation of 1,2,3-thiadiazol-5-yl ureas | |
| CA1131639A (en) | Process for the manufacture of 1,2,3-thiadiazol-5-yl ureas | |
| Harris Jr | The reactions of sulfenyl chlorides with thionocarbamates | |
| CA1077045A (en) | Process for the manufacture of 5-amino-1,2,3-thiadiazole | |
| US4132736A (en) | Preparation of 4-alkylthiosemicarbazides | |
| US3139455A (en) | Phenoxyacetamidoximes | |
| US4200757A (en) | Process for the production of 3-aminoisoxazoles | |
| US4581175A (en) | N'-acylhydrazine-N-thiocarboxylic acid O-carbamoylmethyl esters | |
| SU856384A3 (en) | Method of preparing derivatives of 1,2,3-thiadiazolin-2-ide | |
| NL8002234A (en) | PROCESS FOR PREPARING 5-MERCAPTO-1,2,3-TRIAZOLS. | |
| SU588918A3 (en) | Method of preparing 2-substituted 1,3,4-thiadiozole-5-thioles | |
| US3725479A (en) | Bis(4-amino-or 4-substituted amino-3,5-dinitrophenyl) disulfide | |
| US4515958A (en) | Process for preparing 1-alkyl-5-mercaptotetrazoles | |
| KR820002276B1 (en) | Process for preparing 1,2,3-thiadiazol-5-yl-ureas | |
| US3705171A (en) | Preparation of 2-substituted-5-amino or substituted amino-1,3,4-thiadiazoles | |
| KR830000271B1 (en) | Method for preparing 1,2,3-thiadiazol-5-yl urea | |
| US3478045A (en) | Production of 5-mercapto-1,2,4-thiodiazole derivatives | |
| US3484452A (en) | 3-amino-4-phenyl-1,2,5-thiadiazole | |
| US2623877A (en) | Sulfa derivatives of 2-amino-5-cycloalkyl-1, 3, 4-thiadiazoles | |
| HU190449B (en) | Process for production of derivatives of acetid acid substituated by phosphorus | |
| US3256269A (en) | Mixed anhydrides of naphthylazophenyl | |
| US3560488A (en) | 3-sulfanilamido-4-substituted-1,2,5-thiadiazoles | |
| KR970006853B1 (en) | 1-££(pyrazolsulfonyl)amino| carbonyl| pyridinium hydroxide and process for the preparation thereof | |
| CA2051338A1 (en) | Process for the preparation of aminopyrimidines | |
| JPS5811434B2 (en) | Method for producing acylhydrazone of formyl acetate |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| MKEX | Expiry |