Note: Descriptions are shown in the official language in which they were submitted.
- ~()7(~696
; The present invention relates to a process for the production of
3-hydroxy-1,2,4-triazole deriva~ives of the formula 1
R~
.~ R2 X C C - OH ~I)
N
. . .
wherein Rl represents an alkyl group having 1 to 6 carbon atoms or a cycloalkyl
group having 3 to 8 carbon atoms, R2 represents an alkyl group having 1 to 6
carbon atoms, a cycloalkyl group having 3 to 8 carbon atoms, an alkenyl group
having 3 to 6 carbon atoms, an alkynyl group having 3 to 6 carbon atoms, or
a benzyl group optionally mono- or di-substituted by alkyl alkoxy or alkylthio
each having 1 to 4 carbon atoms, or by halogen, trifluoromethyl or nitro, and
X represents oxygen, sulphur or a group ~N-R3, wherein R3 denotes an alkyl
group having 1 to 6 carbon atoms, an alkenyl group having 3 to 6 carbon atoms
or an alkynyl group having 3 to 6 carbon atoms.
The 3-hydroxy-1,2,4-triazole derivatives of the above
. .
:
, . .
., .
,.
,
:~
: .~
-1 ~
~ B -2-
, . - . . , : . ' : '
.,, , . , . . . , ~ , .
' ' ' , ' ' " ' ' : , , ,
1070696
formula I are valuable intermediates for the production
:~ of phosphoric acid esters which can be used as pest-
: ~ control agents, eo~cci~l ~ as insecticides. Such phosphoric
acid esters are described, for example, in the German
5 'Offenlegungsschriften' Nos. 2,259,960, 2,259,974 and
2,330,089.
It is known that 1,5-disubstituted 3-hydroxy-1,2,4-
triazoles of the above formula I can be produced by
~: reaction of a sèmicarbazide, substituted by the radical
Rl according to the aforementioned definition, with
orthoformic acid ester, subsequent chlorination in the
5-position of the initially resulting 3-hydroxy-1,2,4-
triazole substituted in the l-position, and replacement of
~'
the chlorine atom by the radical R2-X-, wherein R2 and X
~: 15 have the meanings given under the formula I. This known
: process requires a large number of reaction steps and, in
~ addition, is unsatisfactory with regard to the attainable
"~7 yields. The losses in yield occur mainly on carrying out
chlorination of the 3-hydroxy-1,2;`4-triazole occurring as
an intermediate and on replacement of the introduced
chlorine by the group R2X-.
. It has now been found that the 3-hydroxy-1,2,4-triazolederivative of the formula I can be produced in a simple
.
. . .
. .
. . .
..... , . ~ . . . . . .
. . . :- , ~ ~ .
. ', .
1070~96
manner by a process in which a hydraæinecarboxylic acid
ester of the formula II
Rl-NH-NH~COOR (II)
wherein Rl has the meaning given under formula I, and
R represents an alkyl radical having 1 to 4 carbon atoms,
is firstly reacted with cyanogen chloride to the corresponding
2-substituted 2-cyanohydrazinecarboxylic acid ester of
the formula III
Rl - N - NH - COOR
C - N (III),
; 10 wher~in Rl and R have the meanings given under the formulae
I and II, and thîs is subsequently cyclised under alkaline
conditions in the presence of a compound R2-X-H.
The process of the invention is advantageously performed
,
in an inert solvent. For the reaction of a hydrazine-
carboxylic acid ester of the formula II with cyanogen
chloride, suitable solvents are, in particular, halogenated
hydrocarbons such as methylene chloride, chloroform,
carbon tetrachloride, chlorobenzene, or aromatic hydrocarbons
such as benzene and toluene, or ketones, especially methyl
ethyl ketone, or esters, particularly ethyl acetate, or
. - ~
':
.' ' , ' ' . ~ ' .
, ' ' . ', ~ ~ :
~070696
ethers and ethereal liquids such as diethyl ether,
tetrahydrofuran and dioxane. For the concluding cyclisation
reation, suitable solvents are, in particular, alcohols
and water, with suitable alcohols being lower alkanols
having 1 to 4 carbon atoms. The cyclisation reaction
can however be performed also in the absence of solvents.
The reaction o a hydrazine carboxylic acid ester of
the formula II with cyanogen chloride is carried out
i~` advantageously in the presence of an acid-binding agent
at a temperature of between 0 and 30C. Suitable acid-binding
agents are, in particular, alkali metal hydroxides, alkali
. ~ .
metal carbonates and especially alkali metal hydrogen
carbonates. It is furthermore advantageous to perform the
reaction of a hydrazine carboxylic acid ester of the formula II
with cyanogen chloride in a two-phase reaction medi~
consisting of water and one of the above mentioned
solvents immiscible with water.
The cyclisation reaction is performed at a temperature
of between 0 and 140C, preferably at 40 to 80C. The
reaction can be carried out at normal pressure or, if
necessary, at excess pressure up to 50 atm. in an auto-
clave. Where the cyclisation reaction is performed in a
lower alkanol, it is advantageous to operate in the presence
_ 5 _ .
. ~ j .
i
,
, . .
.. ..
,
.. . , ~
1070696
~f the corresponding sodiu~ or potassium alcoholate. The
cyclisation reaction in a lower alkanol can rnoreover by
carried out also in the presence of sodium hydroxide or
potassium hydroxide. In the case where the cyclisation
S reaction is performed in water, it is preferable to
operate in the presence of sodium hydroxide or potassium
hydroxide.
The radicals Rl and R2 comprise as alkyl groups
straight-chain and branched-chain alkyl radicals having
1 to 6 carbon atoms. As cycloalkyl groups having 3 to
carbon atoms, the radicals Rl and R2 comprise also
cycloalkyl radicals substituted in the ring by lower alkyl
groups. In addition, these cycloalkyl radicals can be
bound by way of 1 to 3 methylene groups to the nitrogen
atom or to X. The radical R2 as a ben~yl group can be
mono- to di-substituted in the benzene nucleus by alkyl,
alkoxy, or alkylthio groups each having 1 to 4 carbon
atoms, halogen, especially chlorine or bromine, nitro
or trifluoromethyl.
The process according to the invention is further
illustrated by the following Examples.
.
, ' :
.,
- :
,
f ,' . ' . ' ' : ' ' ' ' .
' ' ' , , ' ` " ' , ' ' ' ' ~ ' , '
, ~ , , .
'' ' ' ' ' ` , ' . ` ' ' ' . ' ' " ''
~ ' ~ . ' ' ~"
' ' ' ' ' ' ";
1070696
Example 1
73.0 g of 2-isopropylhydrazinecarboxylic acid ethyl
; ester and 42.0 g of sodium bicarbonate are stirred into
200 ml of methylene chloride and 400 ml of water. There
is then introduced at room temperature in the course of
20 minutes, wi~h continuous stirring, 30.8 g of gaseous
cyanogen chloride. After an hour's stirring, the methylene
chloride base is separated, dried over sodium sulphate
and the solvent is distilled off in vacuo. There is
obtained as residue 75.0 g (87.5% of theory) of 2-isopropyl-
2 cyanohydrazinecarboxylic acid ethyl ester as co]ourless oil.
1370 g of 2-isopropyl-2-cyanohydrazinecarboxylic acid
` ethyl ester is placed into an autoclave, and 423 g of
methyl is injected. The temperature is held for 24 hours
at 40C. Yhe resulting crystal mass is afterwards transferred
to a 2.5 litre sulphonating flask, and heated i~ an oil
bath for 2 1/2 hours at 120C. There is then added to the
- reactiorL mixture cooled to 90C 1.2 litres of wa~er,
whereupon the the reaction product precipitates in crystalline
form. Crude l-isopropyl-S-methylthio-3-hydroxy-1,2,4-
~hiazole is filtered off, and recrystallised from one litre
of acetonitrile~ There is obtained 730 g (52% of theory)
of pure l-isopropyl-5~methylthio-3-hydroxy-1,2,4-triazole,
m.p. 88-93C _ 7
.
,
.~ ,
,,. , - :
' .
,, ' . -'"'`''''' ~ ;. .. .
.. ~ ' - .
~:
1070696
Example 2
960 g of methyl mercaptan is lntroduced into a solution
of 800 g of sodium hydroxide in 5000 ml of water, and
3024 g of 2-isopropyl-2-cyanohydrazinecarboxylic acid
ethyl ester is subsequently added dropwise. During the
dropwise addition, the temperature rises to 80C and
is then maintained for 2 hours at 80C. Stirring is
afterwards continued for 15 hours at 20C. After the
addition of 1200 g of glacial acetic acid, 2872 g of
l-isopropyL-S-methylthio-3-hydroxy-1,2,4-triazole,
m.p. 93-96C, precipitates. From the filtrate there is
obtained, by extraction with ethyl acetate, a further
175 g if 1-isopropyl-5-methylthio-3-hydroxy-1,2,4-triazole.
; The total yield is therefore 3047 g (87.5% of theory).
'. .. ' . .
: . , : ' ' ,'
. . - - . .
. . ', . .:
1070696
Example 3
66.0 g of 2-ethylhydrazinecarboxylic acid ethyl ester
and 42.0 g of sodium bicarbonate are stirred into 200 ml
- of methylene chloride and 400 ml of wa~er. There is
then introduced at room temperature in the course of
20 minutes, with continuous stirring, 30.~ g of gaseous
cyanogen chloride. After one hour's subsequent stirring,
the methylene ch]oride phase is separated and dried over
sodium sulphate, and the solvent is distilled off in vacuo.
There is obtained as residue 69.0 g ~88% of theory) of
2-ethyl-2-hydraæinecarboxylic acid ethyl ester as
colourless oil.
To a solution of 4.6 g of sodium in 150 ml of absolute
ethanol there is added dropwise at 60C 31.4 g of
2-ethyl-2-cyanohydrazinecarboxylic acid ethyl ester. The
solution is subsequently refluxed for 4 hours. ~rom the
cooled solution there precipitates, after the adfiition of
12 g of glacial acetic acid, sodium acetate, which is
separated by filtration. The filtrate is concentr&ted in
vacuo to dryness, and the residue is extracted with 200 ml
of chloroform. The extract is again concentrated to dryness
and the residue is recrystallised from cyclohexane. There is
obtained 18.8 g (60% of theory) of 1-ethyl-5-ethoxy-3-hydroxy-
1,2,4-triazole, m.p. 64 to 6~C.
'.
~.
1070696
Example 4
35.0 g of 2-isopropyl-2-cyanohydrazinecarboxylic acid
ethyl ester is added dropwise to a solution of 100 ml
of 33% dimethylamine in absolute e~hanol. The solu~ion
is maintained firstly for lS hours at room temperature
S and afterwards for 1 1/2 hours a~ reflux temperature
(65C). After concentration by evaporation ~o dryness
there remains an oily residue, which slowl.y crystal]ises
on standing. The semisolid product is washed with e~hyl
acetate. There is obtained 15.5 g (44% of theory) of
l-isopropyl 5-dimethylamino-3-hydroxy-1,2,4-triazole,
m,p. 111-112C.
. , ' .
,.,
.. .
:'...
. . .
- 1 0
,~ .
. ~; .
. . .
.
...... ~ . . . ~ - -
:, . . ' - , , ' . ", ,
, i - ~ ' . ,:
.
1070696
Example 5
48 g of methyl mercaptan is introduced into a solution
of 40 g of sodium hydroxide in 300 ml of water, and 185 g
of 2-sec.butyl-2-cyanohydrazinecarboxylic acid ethyl ester
is subsequently added dropwise. The temperature rises to
90C during the dropwise addition. The mixture is then
allowed to cool to room temperature. After the addition
of 60 g of glacial acetic acid, there precipitates
148.9 g (79.5% of theory) of 1-sec.butyl-5-methylthio-3-
hydroxy-1,2,4-triazole, m.p. 104-106C.
The 2-sec-butyl-2-cyanohydrazinecarboxylic acid ethyl
ester used as starting material is produced by methods
analogous to those given in Examples 1 and 3 by reaction
of 2-sec.butylhydrazinecarboxylic acid ethyl ester with
. cyanogen chloride.
`:
i
'' .
, , - 11 -
., . ~ ~ .
~070696
Example 6
905 g of methyl mercaptan is introduced into an
ethanolic solution of sodium ethylate produced from
361 g of sodium and 9 litres of absolute ethanol, and
an addition is subsequently made of 2470 g of 2-ethyl-
2-cyanohydrazinecarboxylic acid ethyl ester. The soLution
obtained is kept firstly for lS hours at room temperature
and then for 3 hours at reflux temperature (80C). After
~he addition of 942 g of glacial acetic acid, there
precipitates from the cooled solution sodium acetate,
which is separated by filtration. The filtrate is
concentrated in vacuo to dryness; the residue is taken
up in 7 litres of chloroform and filtratlon is performed.
The filtrate is concentrated by evaporation at normal
pressure and toluene is added; ~iltration is carried out ,
and 1 litre of cyclohexane is added to the filtrate. There
is obtained 1890 g (75.5% of theory) of 1-ethyl-5-methyl
thio-3-hydroxy-1,2,4-triazole, m.p. 83-87C.
.
,, ~
- 12
~,
' .
. , '. " ~ ' ,. ,. ' ~,, "', ,~ ;.'' . ', ,
~070696
,
Rxample 7
To an ethanolic solution of sodium ethylate produced
from 4.6 g of sodium and 100 ml of absolute ethanol
there is firstly added dropwise 14.9 g of ethyl mercaptan
and subsequently 31.4 g of 2-e~hyl-2-cyanohydrazine-
S carboxylic acid ethyl ester is added dropwise. There isformed a crystalline precipitate, which is refluxed for
3 hours. The cooled suspension is freed, after the addition
of 12 g of glacial acetic acid, by filtration from the
- precipitated sodium acetate, and the filtrate is concentrated
in vacuo to dryness~ 200 ml of chloroform is added to the
residue and filtration is performed. The filtrate is
again concentrated to dryness. The residue is recrystalli~ed
with cyclohexane. There is obtained 26 g (75~/O of theory)
of l-ethyl-5-ethylthio-3-hydroxy-1,2,4-triazole, m.p. 65-68C~
,, .
.
... .
- 13 -
'~ .
:'
' J' '
:~ ~
~070696
ExamPle 8
51.5 g of ethyl mercaptan and subsequently 163 g of
2-cyclopentyl-2-cyanohydrazinecarboxylic acid ethyl ester
are added dropwise to a solution of 33~2 g of sodium
hydroxide in 190 ml of water at room temperature. The
S solution is subsequently refluxed for 1 hour. From the
cooled solution there precipitates, after the addition
: of 50 g of glacial acetic acid~ 167 g (94% of theory)
of l-cyclopentyl-5-methylthio-3-hydroxy-1~2~4-triazole,
m-p~ 93-95C.
. lO The 2-cyclopentyl-2~cyanohydrazinecarboxylic acid ethyl
ester used as starting material i9 produced by a method
analogous to that described in the Examples l and 3 by
~: reaction of 2-cyclopentylhydrazinecarboxylic acid ethyl
ester with cyanogen chloride.
;'. .
.
P.
''..~
...
.
..:
.~ ,
~; . . : :
, . , ~ ' .
~0706g6
~ Exam~ 9
.
244 g of allyl mercaptan is added to a solution of
132 g of sodium hydroxide in 750 ml of water, and
- subsequently at room temperature 514 g of 2-ethyl-2-
cyanohydrazinecarboxylic acid ethyl ester is added
dropwise. After one hour's refluxing, there is added
to the cooled solution 198 g of glacial acetic acid.
i'.
.- The oily phase is separated and concentrated in vacuo to
dryness. There is obtained 260 g (43% of theory) of
l-ethyl-5-allylthio-3-hydroxy-1,2,4-triazole, m.p~ 74-76C.
,, .
~.'
. ~ .
.
".'
~;' ;
~ - 15 -
.' .
,~ .
.
.`'' ' .. .. . .
i~ :
1070696
Example 10
31.7 g of 4-chlorobenzyl mercaptan is added -~o a
solution of 8 g of sodium hydroxide in 100 ml of water
and 50 ml of alcohol, and subsequent]y 34.2 g of
2-isopropyl-2 cyanohydrazinecarboxylic acid ethyl ester
~, 5 is added dropwise. The temperature rises to 38C during
the dropwise addition. The temperature is then maintained
for 2 hours at 85C. After cooling of the mixture to 20C,
12 g of glacial acetic acid is added dropwise, whereupon
white crystals of l-isopropyl 3-hydroxy-5 (4-chlorobenzyl-
` 10 thio) 1,2,4-triazole precipitate. These are recrystallised
in 400 ml of methanol and yield 42 g of product, m.p.
140--141C (74% of theory).
.
. .
. i , .
. .
, j. .
.
: .
.
; - 16 -
. .
, :
. ,,
.: . - ,
. .' . .
'' ' ' : ' ~ '
- '~
~o706s6
F.xample Ll
To a solution o 8 g of sodium hydroxide in 100 ml
of water and 50 ml of alcohol there is firstly added
24.8 g of benzyl mercapta,n, and subsequently 34.2. g of
2-isopropyl-2-cyanohydrazinecarboxylic acid ethyl ester
'~ 5 is added dropwise. The temperature rises to 38C during
the dropwise addition. The temperature is then held for
2 hours at 85C. After cooling to 20C, there is added
dropwise 12 g o~ glacial acetic acid, whereupon white crystals
of 31 g of 1-isopropyl-3-hydroxy-S-benzylthio-1~2,4-
triazole, m.p. 134-135C, precipitate (62% of theory).
.~
;
- 17
. .
.
1~70696
. .
Example 12
24.05 g of methyl mercaptan is introduced into a
solution of sodium ethylate produce~ by dissolving
11.5 g of sodium in 300 ml of absolute ethanol. There
. . .
is then added dropwise at 60C 71.5 g of 2-cyano-2-
methyl-hydrazinecaxboxylic acid ester, whereupon the
temperature rises to 75C. After completion of the
addition, the reaction mixture is refluxed for 5 hours.
30 g of glacial acetic acid is subsequently added
dropwise to the solution cooled to room temperature. After
separation of the resulting precipitate by filtration,
the solvent is removed in vacuo from the iiltrateO With
dry-ice cooling, the residue is recrystallised from 140 ml
of methanol. Thexe is obtained 21.8 g of 1-methyl-5-methyl
thio-3-hydroxy-1,2,4-triazole (30% of theory) having a
melting point of 128-130C.
The 2-cyano-2-methylhydrazinecarboxylic acid ethyl
ester required as starting material is produced by a
method analogous to that described in Examples 1 and 3
by reaction of 2~methylhydrazinecarboxylic acid ethyl
ester with cyanogen chloride.
- 18 -
:' -
.. . .
