Note: Descriptions are shown in the official language in which they were submitted.
1~743~3
The present invention relates to processes for the
production of new triazole derivatives and their acid
addition salts, to these new substances themselves
and to pharmaceutical compositions containing thcm,
as well as to the therapeutic application of the new
substances.
The new triazole derivatives according to the invention
correspond to the general formula I
7~ ~N
~ ~C~ N (I)
~\
where~n
Rl represents hydrogen, lower alkyl, hydroxymethyl, lower
alkanoyloxy methyl, lower alkoxy methyl, formyl, car-
boxy, lower alkoxy carbonyl, cyano or a group of the
partial formula I aa
¦1 / 4
- C - N (I aa)
\ R
- 2 -
1~74;~3
in which X represents oxygen or two hydrogen atoms
and R4 and R5 each independently represent hydrogen,
lower alkyl having at most 3 carbon atoms, or together
with the adjacent nitrogen atom, they represent mor-
pholino, l-pyrrolidinyl, or piperidino,
R2 represents lower alkyl,
R3 represents hydrogen or lower alkyl or together with
the ad~acent nitrogen atom they represent morpholino,
l-pyrrolidinyl or piperidino
the rings A and B independently of each other are unsub-
stituted or 8ubstituted by halogen up to atomic
number 35, trifluoromethyl, nitro, lower alkyl or
lower alkoxy,
and the~r addition salts.
In the triazole derivatives of the general formula I,
Rl as lower alkyl i8, e.g., ethyl, propyl, butyl, isob~tyl,
pentyl, isopentyl, neopentyl (2,2-dimethylpropyl), hexyl or
isohexyl and, in particular, methyl; as lower alkanoyloxy-
methyl it i8, e.g. formyloxymethyl, propionyloxymethyl, buty-
ryloxymethyl, pivaloyloxymethyl and, in particular, acetoxy-
methyl; and as lower alkoxymethyl it is, e.g. methoxy-, ethoxy-,
propoxy-, isopropoxy-, butoxy-, isobutoxy-, sec.butoxy-,
pentyloxy-, isopentyloxy-, neopentyloxy-, hexyloxy- or iso-
hexyloxymethyl. As lower alkoxy alkoxycarbonyl Rl is, e.g.
propoxycarbonyl, butoxycarbonyl, isobutyloxycarbonyl,
1~74313
pentyloxycarbonyl, isopentyloxycarbonyl, hexyloxy-
carbonyl and, in particular, methoxycarbonyl or
ethoxycarbonyl; and, optionally, mono- or disubsti-
tuted carbamoyl. Substituents of carbamoyl groups
Rl as well as of aminomethyl groups Rl are on the
one hand, lower alkyl, e.g. propyl, isopropyl, butyl,
isobutyl, sec.butyl, pentyl, isopentyl, neopentyl,
hexyl or heptyl, and especially methyl or ethyl.
-- 4 --
~'
,. ,j,~
1~743i3
The lower alkyl R2 and the radical R3 as
lower alkyl are, for example, propyl, isopropyl, butyl,
isobutyl, sec.butyl, pentyl, isopentyl, neopentyl,
hexyl or heptyl, and particularly methyl or ethyl.
Where reference is made in the foregoing and
in the following to lower groups, then those meant are
groups having at most 7 carbon atoms and preferably at
most ~ carbon atoms.
The rings A and B can each on its own be re-
peatedly substituted: but ring A is preferably monosubsti-
tuted and ring ~ preferably unsubstituted or disubstituted
and, in particular, monosubstituted. The substituents are,
for example, halogen up to atomic number 35, trifluoromethyl,
1~74313
nitro, lower alkyl or lower alkoxy. A substituent of the
ring ~ is preferably in the 4-position with respect to
the triazole ring, and the substituent(s) of the ring B
in the onP (or in both) ortho-position(s) with respect
to the carbonyl group. Halogen atoms as substituents
of the rings A and B are fluorine, chlorine or bromine
atoms; lower alkyl is, for example, methyl, ethyl,
propyl, isopropyl, butyl, isobutyl, tert.butyl, pentyl,
isopentyl, neopentyl, tert.pentyl, hexyl or heptyl; and
lower alkoxy is, for example, methoxy, ethoxy, propoxy,
isopropoxy, butoxy, isobutoxy, pentyloxy, isopentyloxy,
hexyloxy or heptyloxy. A substituent of the ring A,
preferably in the 4-position to the triazole ring, is,
in particular, one of the mentioned halogen atoms,
especially chlorine, also nitro or trifluoromethyl. The
ring ~ is preferably unsubstituted, or substituted by
fluorine, chlorine, bromine or trifluoromethyl in any
position, particularly, however, by fluorine or chlorine
in the o-position.
The triazole derivatives of the general formula I
and their addition salts with inorganic and organic acids
possess valuable pharmacological properties. They have,
in particular, an anticonvulsive action, as can be veri~ied,
-- 6 --
1~74313
. .
for example, on the mouse in the pentetrazole convulsion
test after administration of oral doses of from about 0.3
mg/kg, as well as in the strychnine convulsion tes~
and in the electroshock test after administration in each
S case of oral closes of from about 1 mg/kg, for example of
1-[2-(o-chlorobenzoyl)-4-chlorophenyl]-5-(morpholino-
methyl)-lH-1,2,4-triazole-3-carboxamide or N,N-dimethyl-
1-[2-(o-fluorobenzoyl)-4-chlorophenyl]-5-[(dimethylamino)-
methyl]-lH-1,2,4-triazole-3-carboxamide. Furthermore,
the triazole derivatives of the general formula I and
their acid addition salts also have a moderate central
depressant action. The mentioned properties, together with
others that can be demonstrated by selected standard tests
lsee W. Theobald and H.A. Kunz, Arzneimittelforsch. 13,
122 (1963) as well as W. Theobald et al., Arzneimittel-
forsch. 17, 561 (1967)1, characterise the triazole
derivatives of the general formula I and their pharmaceut-
ically acceptable addition salts with inorganic and organic
acids as being active substances for anticonvulsants
and tranquillisers which are usable for the treatment of
epilepsy and of conditions of tension and agitation.
Various triazole derivatives of the general formula I
are moreover suitable as intermediates for the production
-- 7 --
.: .
. ' ':
.
-
1~74313
of further compounds embraced by this general formula.
The invention relates, in particular, to triazole
derivatives of the general formula I in which Rl, R2
and R3 have the meanings given under this formula, ring A
is 6ubstituted in the ~-position with respect to the
triazole ring by halogen up to atomic number 35, especially
-- 8 --
. ~
1~743~3
by chlorine, or by nitro or trifluoromethyl, and ring B
i8 unsubstituted, or substituted in any position by
halogen up to atomic number 35 or by trifluoromethyl,
preferably however by fluorine or chlorine in the ortho-
position .
Triazole derivatives of the general formula I wherein
:. ~
. :
10743~.3
Rl represents hydroxymethyl, formyl, carboxy or lower
alkoxycarbonyl, while R2 and R3 have the meanings
given under formula I or preferably the more restricted
meanings given in the foregoing, and the rings A and B
can be substituted as given under formula I, preferably
however in the manner previously specified, are especially
important as intermediates for the production o~ other
pharmacologically valuable compounds embraced by the
general formula I, as well as of other such compounds.
Compounds of the general formula I having a carboxy group
or lower alkoxy carbonyl group as Rl are of particular
importance as intermediates on account of the ease with
which they can be produced.
The data given in the foregoing relate likewise to
the addition salts of the stated triazole derivatives
embra~ed by the general ormula I with inorganic and
organic acids, especially to the pharmaceutically
acceptable acid addition salts.
The new triazole derivatives of the general formula I
B ~h~ drde~ ~c~/~ ~cc~y~7~
~20 and their~acld a ition sa ts are'produced according to
the invention by a process wherein
a) a reactive ester of a compound of the general
- 10 -
' ~ , ' :, :''~ '
~743~3
formula II
IR
~C~
N _ ~
H2 OH
CO (II)
selected from the group consisting of hydrohalic acid
esters and sulfonic acid esters, in which Rl has the
meaning given under formula I, and the ring~ A and
B are as hereinbefore defined, i8 reacted with
a co~pound of the general formula III
~ R (III)
whereln R2 and ~3 have the meanings given under formula I,
or with an aIkali metal derivative of such a compound
in which R3 has a meaning other than hydrogen; or
b), for the production of compounds of the general formula I
wherein R2 and R3 represent methyl, ~hile Rl has the
meaning given under formula I, a compound of the general
formula IV
-- 11 --
' ~ :
io743i3
~,C ~
I, Ic
~ C N / (IV)
in which Rl has the meaning given under formula I~ and
the rings A and B are as hereinbefore defined
is reacted with for~aldehyde and formic acid, or
c), for the production of compounds of the general formula
I wherein Rl has the meaning given under formula I with the
exception of hydroxymethyl, while R2 and R3 have the meanings
given under formula I, a compound of the general formula V
~,C ~
C 2 \ (V)
CH-OH
,~
- 12 -
1~743~3
in which
Rl, R2 and R3 have the meanings given under formula I,
and the rings A and B are as hereinbefore defined
is oxidised; or
d), for the production of compounds of the general
formula I wherein Rl represents carboxy or lower alkoxy-
carbonyl, while R2 and R3 have the meanings eiven under
formula I, a basic medium is allowed to react with a
co~pound of the general formula VI
fO-O-R6
C~O-O-R6
N NH
Il I
2-N ~ 2 (~I)
CO
in which
R6 represents lower alkyl,
R2 and R3 have the meanlng~ given under formula I, and
the rings A and B can be substituted as defined there;
and, optionally, a compound I obtained by any one of the
- 13 -
,
, ' ' ' ~ ', :
1~374313
n~ ~ p~ay~n~C~t, c ~ p~L/~
V ~ processes given under a) to d) is converted into~r
addition salt with an inorganic or organic acid.
In tria~ole derivatives embraced by the general
formula I, it is possibl.e, within the limits of the
definition for these compounds, to introduce, split off
or modify substituents in the usual manner, i.e. to
convert triazole derivatives of the general formula I
in the usual manner into other final materials o the
general formula I as defined. Thus, compounds of the
general formula I are obtained by a process wherein
e), for the production of compounds of the general
formula I wherein Rl represents optionally mono- or
disubstituted carbamoyl, while R2 and R3 have the meanings
given under formula I, a carboxylic acid of the general
formuLa I e embraced by the general formula I
0 0~1
~C~
N
Cll ~ 2 ( I e)
- 14 -
1~74~13
in which R2 and R3 have the meanings given under formula
I, and the rings A and B are as hereinbefore defined,
or a reactive functional derivative of such a carboxylic
acid, is reacted with a compound of the general for-
mula VII
/ 4
H - N (VII)
R5
in which
R4 and R5 each independently represent hydrogen or
hydrocarbon radicals each having at most 10
carbon atom6, which, provided that they represent
lower alkyl, can also be bound directly together,
or they can be bound in the ~- or y-po6ition by
way of oxygen, sulphur, the imino radical or
a lower alkylimino radical,
or with a reactive functional derivative of
such a compound; or
f), for the production of compounds of the general for-
mula I wherein Rl is aminomethyl or mono- or disubsti-
tuted aminomethyl, while R2 and R3 have the meanin8s given
under the general formula I, a reactive ester of a compound
of the general formula I f embraced by the gener~1 formula I
~o743~3
fH2-OH
~C ~
2 N - R (I f)
~3
in wh~ch R2 and R3 have the meanings given under formula I,
and the rings A and B are as hereinbefore defined, is
reacted with a compound of the general formula VII
given above, wherein R4 and R5 have the meanings given
under this formula, or with an alkali metal derivative
of such a compound; or
g), for the production of a triazole derivative of the
general formula I wherein Rl represents hydroxymethyl,
whlle R2 and R3 have the meanings given under formwla I,
a co~pound of the general formula VIII
- 16 -
~74313
CH2-0-Ac
~C \
11
2 N \ (VIII)
CO
in which
Ac represents the acyl radical of an organic acid, R2 and
R3 have the meanings eiven under formula I, and the rings
A and B are as hereinbefore defined, is solvolysed; or
h), for the production of a triazole derivative of the
general formula I wherein Rl represents formyl, while
R2 and R3 have the meanings given under formula I, a
compound of the gener~l formula I h
Cl H2-()H
~`
D
~ CH2 N \ tI h)
~1~74313
in which R2 and R3 have the meanings given under formula I,
and the rings A and B are as hereinbefore defined, is
oxidised, or
i), for the production of a triazole derivative of the
general formula I wherein Rl represents cyanc, while
R2 and R3 have the meanings given under formula I,
a compound of the general formula I i
I O-NH2
~C\
N N
R C R2
\ CH2-N / (I
CO
in wh~ch R2 and R3 have the meaning~ given under formula I,
and the rlngs A and B are as hereinbefore defined, is
dehydrated, or
J), for the production of triaæole derivatives of the
general forml~la I wherein Rl represents optionally mono-
or disubstituted carb~moyl, while R2 and R3 have the
- lô -
1074313
meanings given under formula I, a compound of the
general formula I ; embraced by the general formula I
CHO
I
N~C~
11
N C R2
~ CO \ CX2-~ / (I J)
in which R2 and R3 have the meanings given under form~la I,
and the rings A and B are as hereinbefore defined, is
reacted with a compound of the general formula VII
previously given, wherein R4 and R5 have the meanings
given under formula VII, in the presence of ~n alkali
metal cyanide and of a ~elective oxidising agent, ~nd,
optionally, a triazole derivative of the general formula I
obtained by any one process or by several successive
proces~e~ according to e) to J) is converted into a pharma-
ceutically acceptable addition salt with an inorganic or
organic acid.
For process a), suitable reactive ester~ of hy-
droxy compounds of the genersl formula II are, for example
-- 19 --
1~74313
hydrohalic acid esters such as chlorides and bromides,
as well as the iodides produced from these, optionally
in situ not until immediately before the subsequent
reaction. Further suitable reactive esters of compounds
of the general formula II are sulphonic acid esters
thereof, particularly lower alkanesulphonic acid esters
such as the methanesulphonic acid esters, and arenesulphonic
acid esters, such as the o- and p-toluenesulphonic acid
esters, the o- or p-nitrobenzenesulphonic acid esters
or the o- or p-chlorobenzenesulphonic acid esters. The
reactions with compounds of the general formula III are
preferably performed in the presence of an acid-binding
agent. As the acid-binding agent, it is possible to use
an excess of the compound of the general formula III, or,
e.g , also a tertiary organic base such as ethyl-
dii.sopropylamine or collidine, or an inorganic basic
substance such as potassium carbonate. The reaction
medium employed can be , e.g., an in~rt, optionally hydrous,
solvent, e.g. a lower alkanol such as methanol, ethanol,
propanol, isopropanol or butanol, a ketone such as acetone
or methyl ethyl k~tone, also, e.g., dioxane, tetrahydro-
furan, dimethylformamide or dim~thylsulphoxide, or an
excess of the compound of the general formula III, as such
or as an a~ueous or organic solution.
- 20 -
' .
1~74313
If there is used as reactant, instead of the
compound of the general formula III, an alkali metal
derivative of such a compound, e.g. a sodium, lithium
or potassi-lm derivative, then as solvent there are
preferably used hydrocarbons such as benzene, toluene
or xylene, ethereal liquids such as 1,2-dimethoxyethane,
tetrahydrofuran or dioxane, acid amides such as dimethyl-
formamide or N,N,N',N',N",N"-hexamethyl-phosphoric acid
triamide, or sulphoxides such as dimethylsulphoxide. The
alkali metal derivatives of such compounds of the general
formula IlI in which R3 has a meaning other than hydrogen
are formed preferably in situ, e.g. by the addition of an
at least equimolar amount of alkali metal hydride such
as sodium hydride, alkali metal amide such as sodium amide
or lithium amide, or of an alkali-metalloorganic compound
such as phenyl- or butyllithium. The reaction temperature
is preferably between 0 and 120C, or it is the boiling
temperature of the reaction medium employed.
Some chlorides of compounds of the general formula II
are described, as intermedia~es, in the German 'Offenlegungs-
schriften'Nos. 2,159,527, 2,215,943 and 2,304,307. Other
reactive esters of compounds of the general formula II
can be produced analogously.
1~74313
In the splitting of the diazepine ring according to
Process b) by means of formaldehyde and formic acid, the
result is not only that the amino group previously
belonging to the diazepine ring is dimethylated, but also
that an optionally present aminomethyl and monosubstituted
aminomethyl Rl is di- and monomethylated, respectively The
splitting according to the process is performed at
elevated temperature, preferably at about 80~C up to the
boiling temperature of the reaction mixture. Although
not absolutely necessary with respect to the overall
balance of the reaction, an appreciable content of
water in the reaction mixture is advantageous; it is
therefore possible to use either a~ueous, e.g., 30 to 36%
~ormaldehyde solution or aqueous, e.g., 85 to 95% formic
acid. The ~ormaldehyde is preferably used in a considerable
cxeess, e.g. two to ~ive times the theoretical amount
of 2 to 4 moles per mole of starting material of the
general formula IV, and the formic acid in an even greater
excess, e.g. two to five times the molar amount
relative to the formaldehyde. Of the starting materials
of the general formula IV, those with hydrogen, carbo~y
or lower alkoxycarbonyl as Rl are described in the Germ~n
'Offenlegungsschriften' Nos. 2,159,527 and 2,215~943,
those with lower alkyl or hydrogen as Rl in the German
. . .
: .,; -. . -
lV74313
'Offenlegungsschriften' Nos. 2,055,889 and 2,159,527,
those with optionally mono- or disubstituted aminomethyl
or with hydroxymethyl as Rl in the German 'Offenlegungs-
~chrift' No. 2,234,652, and those with optiona]ly mono-
S or disubstituted carbamoyl or with formyl as Rl in the
German 'Offenlegungsschrift' No. 2,304,307. Further
compounds of the general formula IV can be produced by
methods analo~ous to those described in the aforementioned
'Offenlegungsschriften'.
The oxidation according to Process c) is performed,
for example, by means of a higher metal oxide such as
chromium trioxide, e.g. ~issolved in acetic acid, or
dissolved in dilute sul~huric acid as oxidation solution
according to Jones and gradually added to the solution
lS o~ the starting material in acetone, at a temperature
o~ between about 0 and 60C, preferably at 2~-30~C;
or with manganese dioxide, particularly in the activated
form d~scribed by J Attenburrow et al., J.Chem. Soc.
1952, 1104, in an inert organic solvent, such as ben~ene
or dioxane, at temperatures of between room temperature
and the boiling temperature o the reaction medium
Starting materials of the general formula V are obtained,
1~37431~
for example, by reduction of reactive esters of compounds
of the general formula II, especially chlorides, with
an alka]i metal borohydride, such as sodium borohydride,
in a lower alkanol such as methanol, or in some other
S suitable organic solvent such as tetrahydrofuran, at
low temperatures, preferably between about -20C and
0C, and reaction of the resulting reduction products
with compounds of the general formula III in a manner
analogous to that in Process a).
Furthermore, starting materials of the general
formula V can be obtained, e.g., also by reduction of compounds
of the general formula I, whereby a suitable reduction
process or catalytic hydrogenation, e.g. in the presence
of Kaney nickel or of a noble metal catalyst, such as
palladiurn on charcoal or on an alkaline-earth metal
carbona~e, can be selected in the case where groups Rl
tha~ are in themselves reducible are to be retained intact.
The oxidation according to c), together with the preceding
reduction, is however more advantageously applied to such
compounds of the general ~ormula I which contain a group ~1
the reduction of which is desired but not possible,
or only possible with difficulty, without the simultaneous
reduction o~ the carbonyl group situated between the
~ngs A and B. For example, a compound of the general
1~74313
formula I in which Rl is disubstituted carbamoyl can
be reduced by means of a complex hydride, such as
lithium aluminium hydride, in an ethereal solvent, such
as tetrahydrofuran, to a compound of the general formula V
in which Rl is the corresponding disubstituted aminomethyl.
In addition, it is possible in an analogous manner to
reduce a compound of the general formula I wherein R
is lower alkoxycarbonyl to a compound of the general
formula V wherein Rl is hydroxymethyl. If the reduction
product is thereupon directly oxidised, then the hydroxy-
methyl group Rl is attacked before the hydroxymet ffllene
group, and there is firstly formed, depending on the
oxidising agent used, a formyl group or carboxyl group Rl,
and immediately afterwards there occurs in the same
operation the oxidation of the hydroxymethylene group to
the carbonyl group. Since compounds of the general formula I
having a carboxy group Rl are more easily obtainable in another
m~nner, particularly the oxidation of a hydroxymethyl group
Rl to ~ formyl group R1 (in an analogous manner to that of
ZO Yroces~ (h~, e.g. by means of the above-mentioned oxidation
solution according to Jones), in the same operation as the ox-
idation of the hydroxymethylene group according to Process c)
ls of practical importance. Alternatively, it is possible in
- 25 -
1~743~3
an above-mentioned reduction product to also firstly
selectively acylate, e.g. acetylate, the hydroxymethyl
group Rl, to then carry out oxidation according to c)
and, optionally, to subsequently again liberate the
hydroxymethyl group according to Process g).
Cyclisation of compounds of the general formula VI
according to d) is performed, e.g., in a diluted aqueous
or aqueous-organic alkali hydroxide solution, especially
sodium hydroxide or po~assium hydroxide solution, as a
basic medium, at room temperature or at moderately
elevated temperatures up to the boiling temperature of
the reaction medium. The organic solvent used is, e.g.,
dioxane or a lower alkanol such as ethanol. If mild
reaction conditions are chosen, e.g. if the at most
double-molar amount, relative to the compound of the
general ormula VI, of alkali hydroxide is allowed to
react at room temperature, and the reaction mixture is
n~utralised before processi~g, then as the main product
there is obtained a triazole derivative of the general
formula I in which Rl is the lower alkoxy carbonyl
corresponding to the group R6; whilst under less mild
conditions the corresponding carboxylic acid, i.e. the com~ou~d
of the general formula I having carboxy as Rl, is obtained.
: . -
''
i~74313
Cyclisation can also be performed by means of an aqueous-
organic ammonia solution as basic medium, e.g. in 2
mixture of concentrated aqueous ammonia and dimethyl-
formamide.
Starting materials of the general formula VI are
obtained, for example, by reaction of the analogous
compounds described, as intermediates, e.g., in the German
'Offenlegungsschriften' Nos. 2,159,527, 2,215,943 and
2,304,307, which compounds contain a halogen atom,
especially a chlorine atom, instead of the disubstituted
amino group, with a compound of the previously given
general formula III in which R2 and R3 have the meanings
defined there, or with an alkali metal derivative thereof,
analogously to Process a) for the production of the
lS tria~ole derivatives of the general ~ormula I. The
simul~ancous occurrence of an aminolysis o~ the carboxylic
acid ester groups is avoided if necessary in the case of
reactions with primary or secondary amines of the general
formula III having lower radicals R2 and R3 by employing
mild reaction conditions and/or only a slight excess of
such amines, or by use of secondary amines in the form of
their alkali metal derivatives.
Process e) is performed by reacting, for example, a
iO~4313
carboxylic acid of the general formula I e with a
compound of the general formula VII in the presence of
a carbodiimide, such as dicyclohexyl-carbodiimide, in
an inert solvent such as tetrahydrofuran. Furthermore,
a carboxylic acid of the general formula I e can be
allowed to react with a lower alkylisocyanate or alkyl-
thiocyanate - as reactive functional derivative of a
compound of the general formula VII - and the
immediate reaction product heated until evolution of
carbo~ dioxide or carbon oxysulphide ceases
Suitable reactive functional derivatives of
carboxylic acids of the general formula I e are, for
example, lower alkyl esters thereof, which can be
reacted with compounds of the general formula VII in
some cases even at room temperature or, where necessary,
wlth heating and, if required, in a closed vessel,
depending on the reactivity and boiling temperature of
the employed compound of the general formula VII As the
reaction medium in this case it is possible to use, e.g.,
a lower alkanol such as methanol or ethanol, or another
inert organic solvent such as tetrahydrofuran or dioxane,
optionally together with an excess of the compound to be
reacted of the general formula VII.
- 28 -
,. .. .
1074313
Further suitable reactive functional derivatives
of carboxylic acids of the general formula I e are
halides thereof, especially chlorides, particularly
in the form of their hydrohalides, such as hydrochlorides.
S These are produced preferably directly before the subsequent
reaction with the compounds of the general formula VII
from the corresponding free carboxylic acids and suitable
acid halides such as thionyl chloride, oxalyl chloride
or phosphorus tribromide, and further reacted without
purification The carboxylic acid halides or their
hydrohalides are reacted with compounds of the general
formula VII, preferably in the presence of the at least
equivalent or at least double-equivalent amount of an
acid-binding agent, e.g. of a strong tertiary organic base
such as triethylamine, N-ethyl-~iisopropylamine, pyridine
or s-collidine, which in excess can also serve as reaction
medium, or in the presence of a corresponding excess of
the compound of the general formula VII to be reacted,
in the presence or absence of an inert organic solvent,
such as dioxane, tetrahydrofuran, benzene or dimethyl-
formamide, at a temperature of between about 0C and
100C, or at the boiling temperature of the reaction
medium in the case where this is lower. It is possible
- 29 -
1~74313
under analogous reaction conditions to react also mixed
anhydrides of carboxylic acids of the general formula I e,
especially the mixed anhydrides with carbonic acid
semi-esters obtainable, e.g., by reaction of alkali
metal salts of such carboxylic acids with chloroormic
acid esters, preferably chloroformic acid lower alkyl
esters, with compounds of the general formula VII.
Further suitable reactive functional derivatives
of carboxylic acid esters of the general formula I e
10 are, e,g., reactive esters such as p-nitrophenyl esters
and cyanomethyl esters, which can be reacted with
compounds of the general formula VTI in inert organic
solvents, if necessary with heating. There are reacted
under the same conditions ~he l-imidazolides of carboxylic
acids of the general formula I e with compounds of the
general formula VII.
As reactive functional derivatives of compounds
of the general formula VII, there have already been mentioned
lower alkylisocyanates and lower alkylisothiocyanates
which are derived from compounds of the general formula
VII havlng a hydrogen a~om as R5. The reactions of these
with carboxylic acids of the general ormula I e can
be performed in the presence or absence of an inert organic
- 3~ -
: :
.~
: :
1~74313
solvent having a sufficiently high boiling point or
boiling range, e.g. toluene or xylene or an xylene
mixture. Further reactive functional derivatives of
compounds of the general formula VII having a hydrogen
atom as R5 are, e.g., the N-tri-(lower alkyl)-silyl
derivatives obtainable by reaction of these compounds
with tri-(lower alkyl)-silyl chlorides, such as
trimethylsilyl chloride, in inert anhydrous organic
solvents, The reaction thereof with reactive functional
derivatives o carboxylic acids of the general formula
I e in inert organic solvents yields N-tri-(lower alkyl)-
silyl derivatives of carboxamides embraced by the
general formula I, from which the desired carboxamides
are liberated by decomposition with water or with
lower alkanols,
~ uitable unctional derivatives of such compounds
o the general formula VII in which neither R4 nor R5
represents hydrogen are, e.g " N-chlorocarbonyl deri~atives
thereof. These are reacted with salts, e,g, alkali metal
salts of carboxylic acids of the general formula I e
in the presence or absence o~ inert organic solvents,
such as toluene or dimethylformarnide, and the reaction
mixtures are heated until the equimolar amount of carbon
1~74313
dioxide is liberated from the primarily formed
carboxylic acid-carbamic acid-anhydrides Likewise
from compounds of the general formula VII wherein
neither of the radicals R4 and R5 represents hydrogen
are derived, e.g., sulphurous acid-monoalkyl ester-
monoamides, which yield, on reaction with carboxylic
acids o the general formula I e in organic solvents,
e.g. in pyridine, dioxane or dimethylormamide or in
benzene, the desired carboxamides embraced by the
general formula I.
Suitable reactive esters of compounds of the general
formula I f are, for example, sulphonic acid esters
thereof, particularly Lower alkanesulphonic acid esters
such as methanesulphonic acid esters, and arenesulphonic
acid e~ters such as o- and p-toluenesulphonic acid
ester6, o- or p-ni~robenzenesulphonic acid estcrs or
o- or p-chloroben~enesulphonic acid esters. Further
suitable reactive esters of compounds of the general
formula I f are hydrohalic acid esters thereof, especially
chlorides and ~romides, as well as the iodides produced
in situ t~erefrom The reactions with compounds o the
general formula VII or with their alkali metal derivatives
can be performed analogously to Process a~.
- 32 -
1074313
The compounds of the general formula I f can be
produced by various processes according to the invention,
e.g. by Process b) if R2 and R3 are to be methyl, and
particularly by Process g), and converted by methods
known per se into reactive esters. A further production
possibility for the organic sulphonic acid esters
embraced also be the general formula VIII of the starting
materials for Process g) is given later on in the text.
In the starting materials of the general formula VIII
for Process g), the acyl radical Ac is preferably the
acyl radical of a carboxylic acid, of a carbonic acid
semi-ester or of an organic sulphonic acid. As an acyl
radical o~ a carboxylic acid, Ac is, e.g., lower alkanoyl
such as formyl, propionyl, butyryl, isobutyryl, valeryl
lS or pivaloyl and, in particular, acetyl, also, e.g.,
halogenated lower alkanoyl such as trifluoroacctyl or
~ri~hloroace~yl, or arenecarbonyl such as benzoyl, p-
chlorobenzoyl or p-nitrobenzoyl. As an acyl radical of a
carbonic acid semi-ester, Ac is, e.g., methoxycarbonyl,
ethoxycarbonyl, propoxycarbonyl, butoxycarbonyl, tert.-
butoxycarbonyl, phenoxycarbonyl or benzyloxycarbonyl,
and as an acyl radical of an organic sulphonic acid, it is,
e.g., lower alkylsulphonyl such as methylsulpl~onyl, or
- 33 -
i874313
arylsulphonyl such as phenylsulphonyl, o- or p-tolyl-
sulphonyl, o- or p-nitrophenylsulphonyl or o- or p-
chlorophenylsulphonyl. The solvolysis of compounds
of the general formula VIII according to g) can be
S performed by methods known per se in a basic or acid
medium, for example in lower-alkanolic or lower-alkanolic-
aqueous alkali hydroxide solutions, at room temperature
up to the boiling temperature of the reaction mixture,
or with aqueous OL' aqueous-organic mineral acids, e.g.
in dilute hydrochloric acid, to which is optionally added
a water-miscible organic solvent such as dioxane,
tetrahydrofuran, methanol or ethanol, at the same
temperatures.
The starting materials of the general formula VIII
are obtained, for example, starting from compounds of
the general formula I wherein Rl is lower alkoxycarbonyl
by simultaneous reduction of this group to the hydroxy-
methyl group and of the carbonyl group situated between
the rings A and B to the hydroxymethylene group by
means of a complex hydride, such as lithium aluminiuAm
hydride, i.n an ethereal solvent, such as tetrahydrofuran,
at a temperature of bet~een about 0~ C and room temperature,
followed by partial acylation of the hydroxymethyl group
1r374313
by methods known per se; and finally oxidation of the
hydroxymethylene group to the carbonyl group, analogously
to the aforementioned Process c) for the production
of compounds of the general formula I.
For the oxidation of triazole derivatives of the
general formula I h to triazole derivatives of the
general formula I having formyl as Rl according to
Process h), there are used mild selective oxidising
agents, such as dimethylsulphoxide, optionally in the
presence of a water-binding agent, such as dicyclohexyl-
carbodiimide and phosphoric acid, at room temperature
or at modera~ely elevated temperatures up to about 100C;
or manganese dioxide, which is preferably activated
according to J. Attenburrow et al., J.Chem.Soc. 1952,
l~ 1104, in an inert organic solvent at a temperature of
between about 50C and the boiling temperature of th2
solvent, e.g. in boiling benzene, The oxidising agent
employed can also be chromium trioxide, e.g. dissolved
in dilute sulphuric acid as an oxidation solution
according to Jones, with this oxidation solution being
slowly added, preferably at between 0C and room temperature,
to ~he solution of ~he starting ma~erial in acelone The
/q l h
starting materials of the general ~e~mula I c are produced
- 35 -
1~743~3
for example, by the aformentioned Process g) or, if
R2 and R3 are methyl, also by Process b).
Dehydration of the triazole derivatives of the
general formula I i according to Process i) can be
performed~ by methods known per se, at room temperature
or at elevated temperatures up to about 180C. For
example, there is allowed to react with a carboxamide
of the general formula I i an organic or inorganic
acid halide, especially a sulphonic acid halide such
as p-~oluenesulphonyl chloride or methanesulphonyl chloride, or
a halide of an acid of trivalent or pentava3.ent phosphorus,
such as phosphorus oxychloride, or an acid anhydrlde,
particularly the anhydride of an inorganic oxygen acid
such as phosphorus pentoxide, in an inert organic solvent
such dimethylformamide or xylene~ The sulphonic ac.id
halid~, such as p-toluenesulphonyl chloride, are uscd
preferably in an equimolar amount or in a moderate excess,
optionally together with a somewhat gre~ter excess of
an acid-binding agent, especially of a tertiary organic
base such as pyridine~ Dehydration can ~or example be
performed at room temperature, or if necessary at slightly
elevated te~peratures, by means of the approx 1.5-fold
molar amount of p-toluenesulphonyl chloride and the app~ox.
- 36 -
'''' ',
' ' '' :" ' :
i~74313
2-fold to 3-fold molar amount of pyridine in dimethyl-
formamide. A further example of a dehydrating agent
to be mentioned is triphenylphosphine, which can be
caused to react, e.g., in a halogenated hydrocarbon,
such as carbon tetrachloride, with a carboxamide of the
general formula I i. The starting materials of the
general formula I i can be produced by a number of the
aforementioned processes, particularly by Process e).
As alkali metal cyanide for Process j), there are
used, for example, potassium cyanide and, in particular,
sodium cyanide. By selective oxidising agents are meant
those which do not under the reaction conditions attack
the aldehycle group of the starting material of formula I j,
but which are able to oxidise the hydroxymethylene group
of the intermediately formed cyanohydrin to the carbonyl
group, A suitable oxidising agent is manganese dioxide,
particularly that in the active form described by J.
Attenburrow et al., J Chem Soc 1~52, 1104 The reactions
wlth manganese dioxide are preferably performed in
isopropanol, or in another lower secondary alkanol, to
which can be added a further organic solvent inert under
the reaction conditions, preferably one having a good
dissolving power for the starting materials of the g~eneral
- 37 -
.: .. . .
.. ~
. .
.:
1074313
formula I j, such as for example dioxane, in the cold
state, e.g. between -10C and +10 C, preferably at about
O~C. Relative to the compound of the general formula I j,
there is used, for example, a considerable excess of
the cornpound of the general formula VII, and also of
alkali metal cyanide, e.g. the approx. 5-fold molar
amount of the latter and an even greater excess, e.g.
the app-rox. 20-fold molar amount, of manganese dioxide,
with a reaction time of 2 to 6, preferably about 4, hours.
The triazole derivatives of the general formula I j, used
as starting materials, are produced, for example, by the
aforementioned Process h), and also by the Process c)
with the use of compounds of the general formula V in
which ~1 represents a hydroxymethyl group.
The present invention relates a]so to such modifi~ations
o~ ~he proc~sses mentioned under a) to j) and to the
preliminary stages thereof, w~lerein a process is interrup~ed
at some stage, or wherein a compound occurring as an
intermedia~e at some stage is used as starting material
and the uncompleted steps are performed, or wherein a
starting material is formed under the reaction conditiolls,
or, optionally, is used in the ~orm of a salt. If the
recluired starting materials are optically active, then ~okh
- 38 -
;, . .. .
. ..
1074313
the racemates and the isolated antipodes can be used,
or in the case of diasteriomeric compounds either mixtures
of racemates or specific racemates, or likewise isolated
antipodes can be used. Also such starting materials can,
S optionally, be used in the form of salts. The starting
materials preferably employed for the carrying out of
the reactions according to the invention are those from
which are obtained the groups of final materials to which
particular reference was made at the commencement of the text.
Depending on the conditions of the process and on
A e no/ p~oo~c~c~
the staLting matcLial~, the starting materials are
obtained in the free form, or in the form, likewise
included in the invention, of their acid addition salts, or
in some cases in the form or hydrates of the last-mentioned
The acid addition salts of the new compounds of the
general formula I can be converted in a kno~m manner
in~o ~he free bases, e.g. with basic agents, such as
alkalies or ion exchangers. Alternatively, the compounds
of the general formula I obtained by the process according
to the invention can, optionally, be converted in the usual
manner into their addition salts with inorganic or organic
acids For examyle, the acid desired as salt component is .
added to a solution of a compound o~ the general formula 1
- 39 -
1~74313
in an organic solvent. Solvents preferably used for the
reaction are those in which the occurring salt is
diificultly soluble, so that the salt can be separated
by filtration. Such solvents are, for example, ethyl
acetate, methanol, ether, acetone, methyl ethyl ketone,
acetone/ether, acetone/ethanol, methanol/ether and
ethanol/ether.
It is possible to use as pharmaceutic active substances,
instead o~ free bases, pharmaceutically acceptable acid
addition salts, i.e. salts with acids of which the anions
are not toxic in the dosage amounts concerned. Moreover,
it is of advantage if the salts to be used as pharmaceutical
active substances readily crystallise, and are not, or
only slightly, hygroscopic. For salt formation with
compounds of the general ~ormula I, it is possible to use,
e.g., hydrochloric acid, hydrobromic acid, sulphuric acid,
phosphoric acld, methanesulphonic acid, ethanesulphonic
acid, 2-hydroxyethanesulphonic acid, acetic acid, lactic
acid, succinic acid, ~umaric acid, maleic acid, malic
acid, tartaric acid, citric acid, benzoic acid, salicylic
acid, phenylacetic acid, mandelic acid and embonic acid
The new compounds can be present, depending on the
choice o~ starting materials and working procedures,
- 40 -
, . ", . ~ . , . ~ .....
,
1874313
as optical antipodes or racemates or, if they have
at least two asymmetric carbon atoms, also as mixtures
of isomers (racemate mixtures). The mixtures of isomers
(racemate mixtures) obtained can, by virtue of the
physical-chemical differences in the constituents, be
separated in a known manner into the two stereoisomeric
(diastereomeric) pure racemates, e.g. by chromatography
and/or fractional crystallisation.
Resulting racemates can be resolved by known
methodæ, for example by recrystallisation from an
optically active solvent, with the aid of microorganisms,
or by reaction with an optically active acid forming salts
with the racemic compound, and separation of the salts
obtained in this manner, e.g. by virtue of their difIerent
degrees of solubility, into the diastereomers from which
the an~ipodes can be libera~ed by the action of suitable
agen~. Particularly suitable optically active acids are,
for example, the D- and L-forms of tartaric acid, di-o-
toluyltartaric acid, malic acid, rnandelic acid, camphor-
sulphonic acid or ~uinic acid. It is of advantage toisolate the more effective of the two antipodes.
The new compounds are administered oral1y, rectally
or parenterally. The dosage amount depends on the mode
- 41 -
1~74313
of administration, on the species, on the age and on
the individual condition. The daily doses of the free
bases or of pharmaceutically acceptable salts thereof
vary between 0.1 mg/kg and 3 mg/kg for warm-blooded
animals. Suitable dosage units, such as dragées, tablets,
suppositories or ampoules, preferably contain 0.5 - 50 mg
of an active substance according to the invention.
Dosage units for oral administration contain as
active substance preferably between 0.5 and 50% of a
compound o~ the general formula I, or of a pharmaceutically
acceptable salt thereof. The said dosage units are
produced by combination of the active substance with,
e.g., solid pulverulent carriers such as lactose,
saccharose, sorbitol or mannitol; starches such as pota~o
starch, maiæe s~arch or amylopectin, also laminaria
po~del^ or citru~ pulp powder; cellulose deriva~ives or
gelatine, optionally with the addition of lubricants,
such as magnesium or calcium stearate or polyethylene
glycols, to form tablets or dragée cores. The dragée
cores are coated, ~or example, with concentrated s-lgar
solutions which can also contain, e.g., gu~ arabic, talcu:n
and/or titanium dioxide, or with a lac4uer ~issolved in
readily volatlle crganic solvents OL- solvent mix~ures.
- 42 -
'' '~;~ ' ' ` .
1~74313
Dyestuffs may be added to these coatings, e.g. for
identification of the various dosage amounts.
Furth~r sui~able oral dosage units are hard gelatine
capsules, as well as soft closed capsu]es made from
gelatine and a softener such as glycerin. The hard
gelatine capsuLes contain the active substance preferably
as a granulate, e.g. in admixture with fillers such
as maize starch, and/or lubricants such as talcum or
magnesium stearate, and optionally stabilisers such as
sodium metabisulphite (Na2S205) or ascorbic acid. In
soft capsules, the active substance is preferably
~ssolved or suspended in suitable liquids, such as in
polyethylene glycols, to which likewise stabilisers
may be added.
15 ~ Suitable dosage units ~or rectal administration are,
e.g., ~uppositories consisting of a combinution of an
active substance with a suppository foundation substance.
Applicable suppository foundation substances are, e.g.,
natural or synthetic triglycerides, paraffin hydrocarbons,
polyethylene glycols or higher alkanols. Also suitable
are gelatine rectal capsules consisting of a combination
of the ac~ive substance wi~h a foundatlon substance.
Suitable foundation subs~ances are, e.g., liquid ~ri-
- 43 -
1074313
glycerides, polyethylene glycols or paraffin hydrocarbons.
Ampoules for parenteral administration, especially
intramuscular administration, preferably contain a
water-soluble salt of an active substance in a concentration
preferably of 0.2 - 5%, optionally together with
suitable stabilisers and buffer substances~ in
aqueous solution.
The following working examples further illustrate
the production of tablets, dragées, suppositories
and ampoules:
a) 50.0 g of 1-12-(o-chlorobenzoyl)-4-chlorophenyl~-5-
(morpholinornethyl)-lH-1,2,4-triazole-3-carboxamide is
mixed with 500 g of lactose and 292 g of potato starch;
the mixture is moistened with an alcoholic solution of
~5 ~ g of gelatine, and then granulated through a sieve.
Af~er drying o~ the granulate, 60 g of potato starch, 60 g
of talcum, 10 g of magnesium stearate and 20 g of highly
dispersed silicon dioxide are mixed in, and the mixture
is subsequently pressed out to form 10,000 tablets each
A ~20 weighing 105.0 mg and each containing 5.0 mg of active
substance; the tablets can be provided with grooves to
effect a more precise adjustment of the dosag~ amount.
- 44 -
:
'
lV74313
b) 2.50 g of N,N-dimethyl~ 2-(o-fluorobenzoyl)-4-
chlorophenyl]-S-(dimethylamino)-methyl]-lH-1,2,4-
triazole-3-carboxamide is well mixed with 15 g of
maize starch and 6 g of highly dispersed silicon
dioxide. ThP mixture is moistened with a solution o~
2 g of stearic acid, 6 g of ethylcellulose and 6 g of
stearin in about 70 ml of isopropyl alcohol, and is then
granulated through a sieve III (Ph.~l~lv. V). The
granulate is dried for about 14 hours and is subsequel~tly
put through sieve III-lIIa. It is then mixed with 16 g
of maize starch, 16 g of talcum and 2 g of magnesium stearate
and the mixture is pressed out to form 1000 dragée cores.
These are coated with a concentrated syrup of 2 g of
lacca, 7.5 g of gum arabic, 0.15 g of dyestuff, 2 g of
highly dispersed silicon dioxide, 25 g of talcum and
53.35 g o sugar, and finall.y dried. The dra&ées obtained
each weigh 162.5 mg and each contain 2.5 mg of active
substance.
c) 10.0 g of 1-l2-(o-chlorobenzoyl)-4-chlorophenyl]-5-
(morpholinomethyl)-lH-1,2,4-triazole-3-carboxamide and
1990 g of finely ground suppository foundation subst~nce
(e.g. cocoa butter) ~re thoroughly mixed and then
melted. From the melt, maintained homogeneo~s by stirring,
- ~5 -
'' ':, `, , ,
,:
i~74;~13
there are formed 1000 suppositories each weighing 2 g
and each containing 10 mg of active substance.
d) A solution of 5.0 g of 1-[2-(o-chlorobenzoyl)-4-
chlorophenyl]-3,5-bis-[(dimethylamino)-methyl]-lH-
1,2,4-triazole-dihydrochloride in one litre of water
is filled into 1000 ampoules and sterilised. Each
ampoule contains 5 mg of active substance as a 0.5%
solution.
The following examples further illustrate the
production of the new compounds of the general formula I
as well as of starting materials not hitherto known, but
t~ey are not intended to limit in any way the scope of
the invention. Temperatures are given in degrees Centigrade.
- 46 -
1074313
Example 1
A mixt:ure o~ 8.~ g (0.018 mole) of 1-(2-benzoyl-
4-clllorophenyl)-5-(iodomethyl)-lH-1,2,4-triazole-3-
carboxylic acid methyl ester and 3.5 ml (0.040 mole)
of morpholine are stirred in 175 ml of methanol at 40
S for 6 hours. The reaction mixture is thereupon concentrated
in vacuo, water is added to the residue, and extraction
is performed twice with methylene chloride. The
organic phase is washed three times with water and once
with saturated sodium chloride solution; it is dried
over sodium sulphate and concentrated in vacuo. The
residue is triturated ~ith ether, whereupon the reaction
product is ohtained in crystalline form. After filtration
with suction and drying in vacuo, there is obtained
1-(2-benzoyl-4-chlorophenyl)-S-(morpholinomethyl)-lH-
I~ 1.,2,4-tria~ole-3-carboxylic acid methyl ester, m.p. 165-170'.
'rhe startin~ material is produced as follows:
a) 224 ml o~ a 6N solution of hydrogen chloride in
methanol is added to a solution of 112.2 g (0.299 mole)
of 1-(2-benzoyl-4-chlorophenyl)-S-(chloromethyl)-lH-1,2,4-
triazole-3~carboxylic acid in 1120 ml of methanol, and
the whole is refluxed for 21 hours. There is then distilled
- 47 -
~' '` ,. "
.
10743~3
off 800 ml of methanol at normal pressure, and the
concentrated solution is allowed to stand for 18 hours
at room temperature. The product that has crystallised
out is filtered off under suction and washed with
cold methanol and hexane. After drying in vacuo, there
is obtained l-(2-benzoyl-4-chlorophenyl)-5-(chloromethyl)-
lH-1,2,4-triazole-3-carboxylic acid methyl ester,
m.p. 132-134~.
b) A solution o~ 51.6 g (0.132 mole) of 1-(2-benzoyl-4-
chlorophenyl)-5-(chloromethyl)-LH-1,2,4-triazole-3-
carboxylic acid methyl ester and 29.8 g (0.198 mole)
of sodium iodide in 1000 ml of acetone is refluxed for
45 minutes. The reaction mixture is thereupon concentrated
in vacuo. Water is added to the residue and extraction
is perormed twice with methylene chloride. The organic
phase is washed once with diluted aqueous sodi~m
bisulphite solution and twice with saturated sodium
chloride solution; it is dried over sodium sulphate and
concentrated in vacuo. The residue is triturated with
ether, whereupon the reaction product crystallises ou~.
After filtration under suction and drying in vacuo, there
is obtained 1-(2-benzoyl-4-chlorophenyl)-5-(iodomethyl)-
lH-1,2,4-triazole-3-carboxylic acid methyl ester, m.p. 139-142~.
- 48 -
.
"' ~ "' '-
1~74313
Example 2
A mixture of 24.0 g (0.050 mole) of 1-(2-benzoyl-
4-chloropl7enyl)-5-(iodomethyl)-lH-1,2,4-triazole-3-
carboxylic acid methyl ester ~see Example la) and b)~
and 20.5 ml of 33% ethanolic dimethylamine solution in
480 ml of methanol is stirred for 2 hours at room
temperature. The reaction solution is thereupon
concentrated in vacuo; water is added to the residue
and extraction is performed twice with methylene
chloride. The organic phase is washed twice with ~ater
1~ and once with saturated sodium chloride solution; it is
dried over sodium sulphate and concentrated in vacuo to
dryness. The amorphous residue is dissolved in 150 ml o~
ether. The reaction product crystallises out whilst the
solution is allowed to stand. The reaction product is
fill:ered off under suc~ion and washed with ether. After
dryin~, there is obtained 1-(2-benzoyl-4-chlorophenyl)-5-
¦(dimethylamino)-methyl]-lH-1,2,4-triazole-3-carboxyl~c
acid methyl ester, m.p. 118-121.
- 49 -
1074313
Example 3
To the solution of 6.0 g (0.0203 mole) of 6-phenyl-
8-chloro-4H-s-triazolo[1,5-a][1,4]benzodiazepine (see
German 'Offenle~ungsschrift' No. 2,159,527) in 27 ml
of 85% formic acid there is added 13.7 ml of 36%
~ueous formaldehyde solution, and the mixture is heated,
with stirring, for 2 hours at 100. The reaction
solution is then allowed to cool to room temperature;
it is poured into ice water, and concentrated sodium
hydroxide solution is added until the pH-value has
reached 11. The precipitated crude product is taken up
in ether. The organic phase is washed twice with water
and once with saturated sodium chloride solution; it
is dried over sodium sulphate and concentrated in vacuo.
The residue is dissolved in 100 ml of ethyl acetate, and
~thereal hydrochlorie acid solution is added until the
pH has reached a value of 3. The hydrochloride precipitates
out in crystallille form. It is filtered off with suction
after 2 hours and wàshed with ether and hexane. There is
obtained 1-(2-benzoyl-4-chlorophenyl)-5-[(dimethylamino)~
methyl]-lH-1,2,4-triazole hydrochloride, m.p. 182-18
with decomposition.
- 50 -
: - .
-.
1~74313
Example 4
13.5 ml of 85% formic acid and 6.7 ml of 36% asueous
formaldehyde solution are added to 3.4 g (0.001 mole)
of ~-phenyl-8-chloro-4H-s-triazolo[1,5-a][1,4]benzo-
diazepine-2-carboxylic acid (see German 'Offenlegungs-
schriften' ~os. 2,159~527 and 2,215,943). The reaction
mixture is subsequently heated, with stirring, at lO0
for 2 hours, in which time the starting product goes
completely into solution. A~ter cooling, there is added
concentrated sodium hydroxide solution until the pH has
reached a value of 5, and the mixture is concentrated in
vacuo to dryness. In order to obtain complete drying, the
residue is concentrated a further three times with a
mixture of toluene/methanol (1:1) in vacuo at 60. The
residue is ex~racted th~ee times with boiling methylene
chloride. The organic phase is concentrated in vacuo,
and the residue is dissolved in 300 ml of ethyl acetate.
The cloudy solu~ion is treated with charcoal and filtel-ed
through Hyflo. A solution of hydrogen chloride in ether
is added to the clear filtrate until an acid reaction to
2G Congo red is indicated. The precipitated crystals are
i]ltered with suction and washed with ethyl ace~ate and
ether. There is obtained 1-(2-benzoyl-4-chlorophenyl)-5-
' , '' .
1~74313
1(dimethylamino)-methyl]-lH-1~2~4-triazole-3-carboxylic
acid hydrochloride, m.p. 160-165 with decomposition.
The following are obtained in an analogous manner:
from 3.25 g (0.001 mole) of 6-phenyl-8-chloro-4H-s-
triazolo[l,5-a3[1,43benzodiazepine-2-methanol:- 1-(2-
benzoyl-4-chlorophenyl~-5-[(dimethylamino~-methyl]-lH-
1,2,4-triazole-3-methanol-hydrochloride;
from 3.43 g (0.001 mole) of 6-(o-fluorophenyl~-8-chloro-
4H-s-triazolo[1,5-a][1,4]benzodiazepine-2-methanol:-
1-[2-(o-fluorobenzoyl)-4-chlorophenyl~-5-[(dimethylamino)-
methyl]-lH-1,2,4-triazole-3-methanol-hydrochloride; and
from 3.59 ~ (0.001 mole) of 6-(o-chlorophenyl)-8-chloro-4H-s-
triaæolo[l,5-a][1,4]benzodiazepine-2-methanol:- 1-[2-
(o-chlorobenzoyl)-4-chlorophenyl]-5-[(dimethylamino)-methyl]-
lS 1,2,4-tri~ole-3-methanol-hydrochloride.
The production of the starting materials is described
in the German 'Offenlegungsschrift' No. 2,234,652.
1C~74313
Example 5
35 ml of 36% aqueous formaldehyde solution is added
~o the solution of 19.2 g (0.050 mole) of N,N-dimethyl-
6-(o-fluorophenyl)-8-chloro-4H-s-triazololl,5-a][1,4]
benzodiazepine-2-carboxamide (see German 'Ofenlegungs-
schrift' No. 2,304,307) in 68 ml of 85% formic acid,
and the mixture is heated with stirring for 2 hours
at 100. The reaction mixture is afterwards cooled to
room temperature; it is poured into ice water, and
concentr~ted sodium hydroYide solution is added until
the pH-value reaches 11. The precipitated crude product
is taken up in methylene chloride. The methylene chloride
solution is washed twice with water and once with saturated
sodium chloride solution; it is dried over sodium sulphate
and concentrated in vacuo. The residue is recrystallised
~rom isopropanol and, after drying in vacuo, there is
~btained N,N-dimèthyl-1-[2-(o-fluorobenæoyl)-4-chlorophen~l]-
S-l(dimethyla.nino)-methyl]-lH-1,2,4-triazole-3-czrboxamidc,
m.p. 140-L42.
The following are obtained in an analogous manner:
from 20.6 g of N,N-diethyl-6-(o-fluorophenyl)-8-chloro-
4H-s-triazolo[1,5-a~[1,4]benæodiazepine-2-carboxamide:
- 53 -
'.' .:
,
1~74313
N,N-diethyl-l-L2-(o-fluorobenzoyl)-4-chlorophenyl]-5-
¦(dimethylamino)-methyl]-lH-1,2,4-triazole-3-carboxamide;
from 20.0 g of N,N-dimethyl-6-(o-chlorophenyl)-8-chloro-
4H-s-triazololl,5-a~[1,4~benzodiazepine-2-carboxamide:-
N,N-dimethyl-1-l2-(o-chlorobenzoyl)-4-chlorophenyl~-5-
l(dimethylamino)-methyl]-lH-1,2,4-triazole-3-carboxamide;
from 21.4 g of N,N-diethyl-6-(o-chlorophenyl)-8-chloro~
4H-s-triazolo~1,5-a]11,4]benzodiazepine-2-carboxamide:-
N,N-diethyl-1-~2-(o-chlorobenzoyl)-4-chlorophenyl]-5-
[(dimethylamino)-methyl]-lH-1,2,4-triazole-3-carboxamidc;
~rom 18.3 g of N,N-dimethyl-6-phenyl-8-chloro-4H-s-triazolo
~ -a][l~4]benzodiazepine-2-carboxamide:- N,N-dimethyl-l-
(2-benzoyl-4-chlorophenyl)-5-l(dimethylamino)-methyl]-lH-
. 1,2,4-triazole-3-carboxamide,
from 19.7 g of N,N-diethyl-6-phenyl-8-chloro-4H-s-triazolo
1l~5-a][l~4]benzodiazepine-2-carboxamide:- N,~-diethyl-l-
(2-benzoyl-4-chlorophenyl)-5-l(dimethylamino)-methyl]-lH-
1~2,4-triazole-3-carboxamide;
from 20.0 g of N,N-dimethyl-6-phenyl-8-(trifluoromethyl)-
411-s-triazololl.,5-a][1,4]benzodiazepine-2-carboxamide:-
- 54 -
1~74313
N,N-dimethyl-1-(2-benzoyl-~ a-trifluoro-p-tolyl)-5-
[(dimethylamino)-methyl]-lH-1,2,4-triazole-3-carboxamide;
rom 18.8 g of N,N-dimethyl-6-phenyl-8-nitro-4H-s-
triazolo[l,5-a~11,4]benzodiazepine 2-carboxamide:-
N,N-dimethyl-1-~2-benzoyl-4-nitrophenyl)-5-[(dimethyl-
amino)-methyl]-lH-1,2,4-triazole-3-carbox&mide;
from 19.7 g of N,N-dimethyl-6-(o-fluorophenyl)-8-nitro-
4H-s-triazolo[l,S-a][1,4]benzodiazepine-2-carboxamide:-
N,N-dimethyl-1-~2-(o-fluorobenzoyl)-4-nitrophenyl]-5-
~(dimethylamino)-methyl]-lH-1,2,4-triazole-3-carboxamide;
from 16.9 g of 6-phenyl-8-chloro-4H-s-triazolo[1,5-a~[1,4]
benzodiazepine-2-carboxamide:- 1-(2-benzoyl-4-chiorophenyl)-
5-L(dirnethylamino)-methyl]-lH-l~2~4-triazole-3-carboxalnide;
from 18.6 g of 6-(o-chlorophen.yl)-8-chloro-4H-s-triazolo
lS l].,S-a]l1,4]benzocli.azepine-2-carboxarnide:- 1-L2-(o-
chlorobenzoyl)-4-chlorophenyl]-5-[(dimethylamino)-methyll-
1}1-1,2,4-triazole-3-carboxamide;
from 17.8 g of 6-(o-fluorophenyl)-8-chloro-4~-s-triazolo
[1,5-a] L 1,4]benzodiazepine~2-carboxamide:- 1-l2-(o-
fluorobenzoy])-4-chlorophenyl]-5-~(dimethylamina)-methyl~
lH-1,2,4-triazole-3-carboxarnide;
' . : . , ~ . ~ ,
1~74313
from 18.5 g of N-methyl-6-(o-fluorophenyl)-8-chloro-4H-
s-triazolo[1,5-a]Ll,4]benzodiazepine-2-carboxamide:-
N-methyl-1-[2-(o-fluorobenzoyl)-4-chlorophenyl]-S-
[(dimethylamino)-methyl]-lH-1,2,4-triazole-3-carboxamide;
from 19.3 g of N-methyl-6-(o-chlorophenyl)-8-chloro-4H-s-
triazolo[l,5-a]11,4]benzodiazepine-2-carboxamide:-
N-methyl-1-[2-(o-chlorobenzoyl)-4-chlorophenyl]-5-
¦(dimethylamino)-methyl]-lH-1,2,4-triazole-3-carboxamicle;
from 19.2 ~ of N-ethyl-6-(o-fluorophenyl~-8-chloro-4H-s-
triazololl,5-a][1,4]benzodiazepine-2-carboxamide:-
N-ethyl-1-[2-(o-fluorobenzoyl)-4-chlorophenyl]-5-[(dimethyl-
amino)-methyl]-lH-1,2,4-triazole-3-carboxamide;
~rom 19.9 g of N-isop~~opyl-6-(o-fluorophenyl)-8-chloro-
. 4H~s-tria~ole [ 1, 5-a ] 11, 4]benzodiazepine-2-carboxamide:-
N-isopropyl-1-¦2-(o fluorobenzoyl)-4-chloropherlyl]-5-
I(dimethylamino)-methyl]-lH-1,2,4-triazole-3-carboxamide;
from 21.3 g of 4-[l6-(o-fluorophenyl)-8-chloro-4H-s-
triazololl,5-a][1,4]benzodiazepin-2-yl]-carbonyll-morpholine:-
4-[[1-~2-(o-fluoroben.zoyl)-4-chlorophenyl]-~-[(dimethyl-
amino)-metllyll-lH-l~2~4-triazol-3-yll-carbonyl~-morpholine;
. , . -
.. ,. ~ .
1~74313
from 20.5 g of 1-~[6-(o-fluorophenyl)-8-chloro-4H-s-
triazolo[l,S-a][1,4Jbenzodiazepin-2-yl]-carbonyl]-
pyrrolidine~ l[l-[2-(o-fluorobenzoyl)-4-chlorophenyl]-
5-l(dime~hylamino)-methyl3-lH-1,2,4-triazol-3-yl]-
carbonyl]-pyrrolidine;
from 21.2 g of 1-[L6-(o-fluorophenyl)-8-chloro-4H-s-
triazololl,5-a][1,4]benzodiazepin-2-yl~-carbonyl]-
piperidine:- l-[[l-12~(o-fluorobenzoyl)-4-chlorophenyl~-
5-l(dimethylamino)-methyl]-lH-1,2,4-triazol-3-yl]-
carbonyl]-piperidine;
from the base liberated from 23.8 g (O.OSO mole) of
1-1[6~(o-fluorophenyl)-8-chloro-4H-s-triazololl,5-a][1,4]
benæodiazepin-2-yl]-carbonyl]-4-methylpiperazine
hydrochloride:- 1-1[1-{2-(o-fluorobenzoyl)-4-chlorophenyl]-
s-l(dinlethylamino)-me~hyl]-lH-l~2~4-triazol-3-yl]-
carbonyl]-4-methylpiperazine and tne dihydrochloride
thereof.
The starting materials used are descri~ed in the
German 'Offenlegungsschrift' No. 2,304,307.
-:
. -. ~..
`
- .
1~74313
Example 6
8.35 ml (about 0.10 mole) of 36% aqueous formaldehyde
solution is added to the solution of the base, liberated
irom ~.30 g (0.010 mole) of 2-[(methylamino)-methyl]~6-
(o-chlorophenyl)-8-chloro-4H-s-triazolo[1,5-a][1,4]benzo-
diazepine-fumarate-(2:1) (see German 'O~fenlegungsschrift'
No. 2,234,652), in 13.5 ml (about 0.25 mole) o~ 85% formlc a~id,
and the mixture is heated, with stirring, for 2 hours at
100. The reaction solution is afterwards cooled to room
temperature; it is poured into ice water, and concentrated
sodium hydroxide solution is added until the pH-value has
reached 11. The crude product that has precipitated is taken
up in ether. The organic phase is washed twice with water
and once with saturated sodium chloride solution; it is
dried ovcr ~odiùm sulphate and then concentrated in vacuo.
~1he oily residue is dissolved in 100 ml of ethanol, and
ethereal hydrogen chloride s~lution is added until the pl~-
~alue has reached 2. The ethanol is thereupon completely
distilled off in vacuo, and ethyl acetate is added to
the residue. The product obtained in crystalline form
is filteL-ed with suction and washed with ethyl acetate
and ether. After drying in vacuum, there is obtained
1-[2-(o-chlorobenzoyl)-4-chlorophenyl3-3,5-bis-(dimethyl-
- 58 -
' '
:
'.
1~74313
amino)-methyl]-lH-1,2,4-triazole-dihydrochloride,
m.p. 100-105 with decomposition.
The following are obtained in an analogous manner:
from the base liberated from 4.30 g (0.010 mole) of
2~ nethylamino)-methyl]-6-(o-fluorophenyl)-8-chloro-4H-s-
triazolo[l,5-a][1,43benzodiazepine-hydrochloride-dihydrate:-
1-[2-(o-fluorobenzoyl)-4-chlorophenyl]-3,5-bis-[(dimethyl-
amino)-methyl3-lH-1,2,4-triazole and the dihydrochloride
thereof.
The following are obtained likewise analogously but,
if desired, with reduction of the amount of 36%
formaldehycle solution to 5.85 ml (about 0.07 mole):
frorn 3.52 g (0.010 mole) of 2-[(dimethylamino)-methyl]-6-
phenyl-8-chloro-4H-s-triazolo[1,5-a][1,4]benzodiazepine:-
lS 1~(2-b~llæoyl-4-chlorophenyl)-3,5-bis-[(dimethylamino)-
me~hyl]-ll-l-1,2,4-triazole and the dihydrochloride thereof;
from 3.~2 g (0.010 mole) of 2-(piperidinomethyl)-6-phenyl-
~-chloro-4H-s-triazolo[1,5-a][1,4]benzodiazepine:-
1-(2-benzoyl-4-chlorophenyl)-3-(piperidinomethyl)-5-
[(dimethylamino)-me~hyl3-lH-1,2,4-triazole and the
dillydrochloride ~hereof;
- S9 -
~ ~', - .,'
`
1074313
from 3.78 g (0.010 mole) of 2~ pyrrolidinyl)-methyl~-
6-phenyl-8-chloro-4H-s-triazolo[1,5-a]11,4]benzodiazepine:-
1-(2-benzoyl-4-chlorophenyl)-3-[(1-pyrrolidinyl)-methyl]
-S-[(dimethyl.amino)-methyl~-lH-1,2,4-triazole and the
dihydrochloride thereof;
from 3.94 g (0.010 mole) of 2-(morpholinomethyl)-6-phenyl-
8-chloro-4H-s-triazolo[1,5-a]l1,4]benzodiazepine:-
1-(2-benzoyl-4-chlorophenyl)-3-(morpholinomethyl)-5-
l(dimethylamino)-methyl]-lH-1,2,4-triazole and the
dihydrochloride thereof; and
from 4.07 g (0.010 mole) of 2-[(4-methyl-1-piperazinyl)-
methyl]-6-phenyl-8-chloro-4H-s-triazolo[1,5-a)11,4]
benzodiazepine:- l-(2-benzoyl-4-chlorophenyl)-3-[(4-
methyl-l-piperazinyl)-methyl~-5-[(dimethylamino)-methyl)-
lH-1,2,4-triazole and the trihydrochloride therPof.
The starting materials used are described in the
; German ' Off enlegungsschrift' No. 2,234,65Z.
:.
"'
- 60 -
. :, .: ~ .. . ...
: , . . . .
- - : . .;
.
. .
1074313
Example 7
7.6 g (0.017 mole) of 1-(2-benzoyl-4-chlorophenyl)-
5-(morpholinomethyl)-lH-1,2,4-triazole-3-carboxylic acid
methyl ester (see Example 1) is covered over with 340 ml
of methanol and 69 ml of concentrated aqueous ammonia
solution. The mixture is heated, with stirring, for
4 hours at 40, with the starting material slowly going
into solution. The reaction mixture is then allowed to
stand for 18 hours at room temperature, and subsequently
concentrated in vacuo. Water is added to the residue and
extraction is performed twice with methylene chloride.
The organic phase is washed twice with ice-cold lN
sodium bicarbonate solution, once with water and once
with saturated sodium chloride solution; it is dried
over sodium æulphate and then concentrated in vacuo to
dryness. The residue is recrystallised from isopropanol
to obtain, after drying in vacuum, 1-(2-benzoyl-4-
chlorophenyl)-5-(morpholinomethyl)-lH-1,2,4-triazole~3-
~ carboxamide, m.p. 146-149.
- 61 -
.
.
- , . , . . - . ,. :
~. , . ., :: . . ,
: : ''~ , . : .
: ;, . ~ - ,.
,, ;j :
. .
.. . .
10743~3
Example 8
17.5 g (0.044 mole) of 1-(2-benzoyl-4-chlorophenyl)-
5-[(dimethylamino)~methyl]-lH-1,2,4-triazole-3-carboxylic
acid methyl ester (see Example 2) is covered over with
850 ml of methanol and 175 ml of concentrated aqueous
ammonia solution. The reaction solution is stirred for
7 hours at room temperature, and afterwards concentrated
in vacuo to dryness. Water is added to the residue, and
extraction is performed twice with methylene chloride.
The organic phase is washed twice with water and once
with saturated sodium chloride solution; it is dried over
sodium sulphate and concentrated in vacuo to dryness.
The residue is dissolved in 300 ml of ethyl acetate,
and ethereal hydrogen chloride solution is added until
the pH-value has reached 2. The crystalline product is
filtered with su~tion and washed with ethyl acetate and
;` ether. After drying in vacuum, there is obtained
1-(2-benzoyl-4-chlorophenyl)-S-[(dimethylamino)-methyl]-
lH-1,2,4-triazole-3-carboxamide-hydrochloride, m.p. 250-
255 with decomposition.
. '
." '
- 62 -
.
' . .,, . ! ' '
1874313
Example 9
9.00 g (0.018 mole) of crude 1-[2-(o-chlorobenzoyl)-
4-chlorophenyl3-5-(morpholinomethyl)-lH-1,2,4-triazole-
3-carboxylic acid hydrochloride is refluxed with 90 ml
of thionyl chloride for 90 minutes. The clear solution
is concentrated in vacuo at 40~ and the residue, in
order to completely remove the thionyl chloride therefrom,
is dissolved in 100 ml of absolute toluene and again
concentrated by evaporation.
The crude acid chloride hydrochloride is covered over
with 90 ml of concentrated aqueous ammonia solution and
the whole is stirred for 18 hours at room temperatllre.
The reaction mixture is afterwards cooled for 2 hours
with ice water; the precipitated crude product is filtered
off, and then well washed with cold water. After
;~ lS recrystallisation from isopropanol there is obtained
1-l2-(o-chlorobenzoyl)-4-chlorophenyl]-5-(morpholinomethyl)-
lH-1,2,4-~riazole-3-carboxamide, m.p. 165-167.
The starting material is produced as ~ollows:
a) 0.10 g of sodium iodide is added to a mixture of
9.3 g (0.0226 mole) of 1-[2-(o-chlorobenzoyl)-4-chloro-
phenyl]-5-(chloromethyl)-1~l-1,2,4-triazolP-3-carboxylic acid
- 63 -
,. .~ ,
. .
.
1~74313
(see German 'Offenlegungsschrift' No. 2,159,527, page 32)
and 9.5 g (O.ll mole) of morpholine in 100 ml of ethanol,
and the whole is refluxed for 2 hours. The reaction
mixture is thereupon concentrated in vacuo; the
residue is dissolved in water, and 2N hydrochloric acid
is added until an acid reaction to Congo red is obtained.
The precipitated hydrochloride of the reaction product
is extracted twice with 100 ml of methylene chloride each
time. A~ter washing with saturated sodium chloride
solution, drying over sodium sulphate and concentration
by evaporation, the organic extracts yield 1-12-(o-
chlorobenzoyl)-4-chlorophenyl]-5-(morpholinomethyl)-
lH-1,2,4-triazole-3-carboxylic acid hydrochloride in the
form of an amorphous yellow foam, which is used directly
~or the next step.
'
- ~4 -
,,
.
.
.
-
1074313
Example 10
The following are obtained analogously to Example 7:
starting with 7.3 g (about 0.017 mole) of crude 1-(2-
benzoyl-4-chlorophenyl)-5-[(1-pyrrolidinyl)-methyl]-lH-
1,2,4-~riazole-3-carboxylic acid methyl ester:- amorphous
1-(2~benzoyl-4-chlorophenyl)-5-[(L-pyrrolidinyl)-methyl]-
lH-1,2,4 triazole-3-carboxamide, of which the hydrochloride,
prepared with ethereal hydrogen chloride solution in
ethyl acetate, melts at 236~ (with decomposition) after
recrystallisation from isopropanol; and
starting with 7.5 g (about 0.017 mole) of crude 1-(2-
benzoyl-4-chlorophenyl)-5-(piperidinomethyl)-lH-1,2,4-
triazole-3-carboxylic acid methyl ester:- crude 1-(2-
benzoyl-4-chlorophenyl)-5-(piperidinomethyl)-lH-1,2,4-
~riazole-3-carboxamide, of which the analogously prepared
hydrochloride melts at 255-260 (with decomposition) ater
recrystallisation from isopropanol.
The starting materials are produced as ~ollows:
a) By a procedure analogous to that of Example 1 there
are obtained, with the use of 2.9 g (0.041 mole) of
pyrrolidine and 3.0 g (0.041 mole) of piperidine,
instead of morpholine, crude l-(2-benzoyl-4-chlorophenyl)-
.; . , . ~ ."., .............. .:,,: :;..... -., -
. ,. . ~
- :, : .
1074313
S-~(l-pyrrolidinyl)-methyl]-lH-1,2,4-triazole-3-
carboxylic acid methyl ester and crude 1-(2-benzoyl-4-
chlorophenyl)-5-(piperidinomethyl)-lH-1,2,4-triazole-
3-carboxylic acid methyl ester, respectively.
''
:
,...
.:,
: - 66 -
. . ~
- . .
: . , : - .. .
.. ; . . . . - , -
. . .
1074313
Example 11
7.0 g (0.0165 mole) of crude 1-(2-benzoyl-4-ni ro-
phenyl)-5-L(dimethylamino)-methyl]-lH-1,2,4-triazole-3-
carboxylic acid ethyl ester (see below) is covered over
with 200 ml of ethanol and 20 ml of conc~ntrated aqueous
S ammonia solutionO The reaction mix~ure is allowed to
stand for 3 days at room temperature, and is then
concentrated in vacuo. Water is added to the residue
and extraction is performed twice with ethyl acetate
The organic phase is washed twice with cold lN sodium
bicarbonate solution and twice with saturated sodium
chloride ~olution; i~ is dried over sodium sulphate and
concentrated in vacuo to dryness. The residue is dissolved
in ethyl acetate/isopropanol (5:1), and the solution is
chrom~tographed on a column of 150 g of silica gel. The
lS eluting agent employed is ethyl acetate/isopropanol (5:1).
The fractions containing the desired product are combined,
and concentrated by evaporation. The residue is recrystal-
lised from ethanol to obtain, after drying in vacuum,
1-(2-benzoyl-4-nitrophenyl) 5-[(dimethylamino)-methyll-lH-
1,2,4-triazole-3-carboxamide, m.p. 187-190.
There is obtained in an analogous m.anner, with the
use of 7.3 g (0.016~ mole) of crude 1-~2-(o-fluorobenzoyl)-
- 67 -
.
: - . . ,
... . . .. ..
.. .. .. . .
1~74313
4-nitrophenyl]-5-l(dimethylamino)-methyl~-lH-1,2,4-
triazole-3~carboxylic acid ethyl ester (see below):
1-l2-(o-fluorobenzoyl)-4-nitrophenyl]-5-[(dimethyl-
amino)-methyl]-lH-1,2,4-triazole-3-carboxamide.
The starting materials are produced as follows:
. .
6 ml (0.072 mole) of 36% aqueous formaldehyde solution
is added to the solution of 7.55 g (0.020 mole) of 6-phenyl-
8-nitro-4H-s-triazolo[1,5-a]~1,4]benzodiazepine-2-
carboxylic acid ethyl ester (see German 'Offenlegungs-
schri~t' No. 2,304,307) in 50 ml of 85% formic acid,
and the mixture is heated for 2 hours at 100. The reaction
mixture is afterwards poured into 200 ml of ice water,
and an undissolved yellow by-product is separated by
filtration through purified diatomaceous earth. Sodium
carbonate is added to the filtrate, with ice cooling,
until the pH-value has reached 9, and extraction is
performed twice with ethyl acetate. The organic phase is
washed twice with water and once with saturated sodium
chloride solution; it is dried over sodium sulphate and
concentrated in vacuo. The residue contains 1-(2-benzoyl-4-
nitrophenyl)-s-[(dimethylamino)-methyl]-lH-l~2~4-triazole
3-carboxylic acid ethyl ester as viscous oil, which is
used directly for ammonol6y8sis.
.
- . , , . .. ~ .
, - -
, ,, -
,. - . . ,, : : . . -
,, - . .
1~743~3
There is obtained in an analogous manner, starting
with 7.91 g (0.020 mole) of 6-(o-fluorophenyl)-8-
nitro-4H-s-triazolo[1,5-a][1,4~benzodiazepine-2-
carboxylic acid ethyl ester, described in the same
'Offenlegungsschrift', 1-[2-(o-fluorobenzoyl)-4-
- nitrophenyl)-5-[(dimethylamino)-methyl]-lH-1,2,4-
~ triazole-3-carboxylic acid ethyl ester.
",
~:'
. -
- 69 -
lV74313
E~xample 12
4.0 ml of 33/0 ethanolic dimethylamine solution is
added to a mixture of 3.75 g (0.01 mole) of 1-(2-benzoyl-
4-chlorophenyl)-5-(chloromethyl)-lH-1,2,4-triazole-3-
carboxamide and 0.15 g of sodium iodide in 70 ml of
; S methanol, and the whole is refluxed for 4 hours with
stirring. The reaction mixture is subsequently concentrated
in vacuo. Water and saturated sodium carbonate solution
- are added until the pH-value has reached 10, and
extraction is performed twice with ethyl acetate. The
organic phase is washed twice with water and once with
saturated sodiurn chloride solution; it is then dried over
magnesium sulphate and filtered. To the filtrate there is
added etllereal hydrogen chloride solution until the pH-
value haY reached 3. The product precipitating in
crystalline form is filtered off with suction and washed
with ethyl acetate and ether. After drying in vacuum, there
is obtained 1-(2-benzoyl-4-chlorophenyl)-5-[(dimethyl-
amino)-methyl]-lH-1,2,4-triazole-3-carboxamide-hydrochloride,
m.p. 250 with decomposition.
The starting material is produced as follows:
a) 30 ml of concentrated aqueous ammonia solution is
- 70 -
, . ~ ,.: , ,,...,- . . .... .. .
,, - - ,.,, " ,, , ::
: : -- :
1074313
added dropwise at 30 in the course of 5 minutes, with
stirring, to the suspension of 6.0 g (0.015 mole) of
1-(2-benzoyl-4-chlorophenyl)-5-(chloromethyl)-lH-
1,2,4-triazole-3-carboxylic acid methyl ester in 220 ml
5 of methanol. There has formed after 4 hours a clear
reac~ion solution, and a short time later a crystalline
product commences to precipitate. Stirring is maintained
for one hour at room temperature and for one hour at
0-5. The formed crystals are thereupon filtered off and
L0 recrystallised from 50 ml of methanol. The product is
filtered off with suction and washed with methanol and
hexane. After drying in vacuum, there is obtained 1-(2-
benzoyl-4-chlorophenyl)-5-(chloromethyl)-lH-1,2,4-
triazole-3-carboxamide, m.p. 128-130.
., . : . . `
1~74313
Example 13
A mixture of 38.7 g (0.075 mole) of 1-[2-(o-ch;oro-
benzoyl)-4-chlorophenyl]-5-(iodomethyl)-lH-1,2,4-
triazole-3-carboxylic acid methyl ester and 13.1 g
(O.lSO mole) of morpholine in 750 ml of methanol is
stirred for 8 hours at 40. The reaction mixture is
then concentrated in vacuo; water is added to the residue
and extraction is performed twice with methylene chloride.
The organic phase is washed three times with water and
twice with saturated sodium chloride solution; it is dried
over sodium sulphate and concentrated in vacuo. The
residue is triturated with ether, whereupon the reaction
product is obtained in crystalline form. After filtration
with suction and drying in vacuum, there is obtained
1-l2-(o-chlorobenzoyl)-4-chlorophenyl]-5-(morpholinomethyl)-
lH-1,2,4-triazole-3-car~oxylic acid methyl ester,
m.p. 141-143.
The following are obtained in an analogous manner:
with the use of 10.7 g (0.15 mole) of pyrrolidine there is
yielded 1-12-(o-chlorobenzoyl)-4-chlorophenyl3-5-l(l-
pyrrolidinyl)-methyll-lH-1,2,4-triazole-3-carboxylic acid
methyl ester;
- 72 -
,,
~ ., ~ . '
i~74313
with the use of 12.8 g (0.15 mole) of piperidine there is
; yielded 1 12-(o~chlorobenzoyl)-4-chlorophenyl]-5-
(piperidinomethyl)-lH-1,2,4-triazole-3-carboxylic acid
methyl ester, and
with the use of 11.0 g (0.15 mole) of diethylamine there is
yielded 1-[2-(o-chlorobenzoyl)-4-chlorophenyl)-5-
l(diethylamino)-methyl]-lH-1,2,4-triazole-3-
carboxylic acid methyl ester.
The 1-l2-(o-chlorobenzoyl)-4-chlorophenyl)-5-(iodomethyl)-
lH-1,2,4-triazole-3-carboxylic acid methyl ester
required as starting material is produced as follows:
a) 270 ml of a 6N solution of hydrogen chloride in methanol
is added to a solution of 133.0 g (0.30 mole) of 1-l2-
(o-ehlorobenzoyl)-4-chlorophenyl]-5-(chloromethyl)-lH-
1,2,4-tria~ole-3-carboxylic acid (crystals containing an
equimolar amount of methanol; see German 'Offelllegungs-
schrift' No. 2,1S~,527, page 32) in 1400 ml of methanol,
and the whole is refluxed ior 18 hours. The reaction
mixture is then concentrated in vacuo; water is added to
the residue and extraction is performed twice with
methylene chloride. The org~nic phase is washed once with
saturated potassi~m bicarbonate solution, twice with water
- 73 -
: , .,
:~ ,:.
~074313
and once with saturated sodium ch1oride solution; it is
subsequently dried over sodium sulphate and concentrated
in vacuo. The residue is recrystallised from 1 litre
of methanol. After drying there is obtained 1-[2-(o-
S chlorobenzoyl)-4-chlorophenyl]-5-(chloromethyl)-lH-
1,2,4-triazole-3-carboxylic acid methyl ester, m.p. 130-132.
b) A solution of 106.2 g (0.250 mole) of 1-[2-(o-chloro-
benzoyl)-4-chlorophenyl]-5-(chloromethyl)-lH-1,2,4-
triazole-3-carboxylic acid methyl ester and 56.2 g
(0.375 mole) of sodium iodide in 2200 ml of acetone is
refluxed for 40 minutes. The reaction mixture is thereupon
concentrated in vacuo. Water is added to the residue, and
extraction is performed twice with methylene chloride.
The organic phase is washed twice with diluted aqueous
sodium bisulphite solution and twice with saturated sodium
chlarlde solution; it is dried over sodium sulphate and
concentrated in vacuo. The residue is dissolved in the
minimum amount of methylene chloride, and 400 ml of ether
is slowly added with stirring, wher~upon the reaction
product crystallises out After filtration with suction
and drying in vacuum, there is obtained 1-12-(o-chloro-
benzoyl)-4-chlorophenyl~-5-(iodomethyl)-1~1-1,2,4-tri~zole-
3-carboxylic acid methyl ester, m.p. 125-128.
. . ..
.
1074313
Example 14
A mixture of 12.90 g (0.025 mole) of 1-12-(o-chloro-
benzoyl)-4-chlorophenyl]-5-(iodomethyl)-lH-1,2,4-
triazole-3-carboxylic acid methyl ester lsee Example
13 b)l and 11 ml of 33~/0 ethanolic dimethylamine solution
S in 250 ml of methanol is stirred ~or 7 hours at room
temperature. The reaction solution is thereupon concentrated
in vacuo; water is added to the residue and the whole
is extracted twice with methylene chloride. The organic
phase is washed twice with water and once with saturated
sodium chloride solution; it is dried over sodium sulphate
and concentrated in vacuo to dryness. The amorphous
residue is dissolved in 130 ml of ether; the solution is
allowed to stand and ~he reaction product then crystallises
out. It is ~iltered of~ with suction and washed with
ether. A~ter drying there is obtained 1-12-(o-chloro-
- benzoyl)-4-chlorophenyl)-5-l(dimethylamino)-methyl]-lH-
1,2,4-triazole-3-carboxylic acid methyl es-er, m.p.
131-134.
- 75 -
, , . ... - .
.. . . . . ; ;- . .... ... . .: ...
1~743~3
Example 15
28.5 g (0.06 mole) o~ 1-[2-(o-chlorobenzoyl)-4-
chlorophenyl]-5-(morpholinomethyl)-1~-1,2,4-triazole-3-
carbGxylic acid methyl ester is covered over with
730 ml of methanol and 290 ml of concentrated aqueous
S ammonia solution. The mixture is heated, with stirring,
~or 4 hours at 40, during which time the starting
material slowly goes into solution. The reaction solution
is then allowed to stand for 18 hours at room temperature
and is subsequently concentrated in vacuo. Water is
added to the residue and extraction is periormed twice
with ethyl acetate. The combined organic extracts are
shaken with ice and and sufficient 2N hydrochloric acid
~olution to bring the p~ value to 3. The hydrochloride,
obtained in crystalline ~orm, is washed with water and
et~yl acetate. The acid aqueous layer is separated from
the filtrate and combined with the suction-filter residue.
There is then added 5N sodiu~ hydroxide solu~ion until the
pH-value has reached 9, and the precipitated ~ase is
dissolved in methylene chloride. The methylene chloride
solution is washed once with water and twice with saturated
sodium chloride solution; it is dried over sodium sulph~te
and concentrated in vacuo. The residue is dissolved in a
- 76 -
, . . -. ., -
. - , ~ . . :,~ . -. . : , :
,..... .. .
., ...... ~ . .. , ,
~- ` -: -
10743~ 3
mixture of methylene chloride and isopropanol; the
methylene chloride is evaporated off at normal pressure,
and cooling to room temperature is effected. The
crystalline reaction product is filtered off with
suction and washed with isopropanol and ether. After
drying in vacuum, the resulting 1-12-(o-chlorobenæoyl)-4-
chlorophenyl]-5-(morpholinomethyl)-lH-1,2,4-triazole-3-
car~oxamide melts at 165-167.
The following are obtained in an analogous manner:
from 27.6 g (0.06 mole) of 1-12-(o-chlorobenzoyl)-4-
chlorophenyl]-5-[(1-pyrrolidinyl)-methyl]-lH-1,2,4-
triazole-3-carboxylic acid methyl ester there is obtained
1-[2-(o-chlorobenzoyl)-4-chlorophenyl]-5-1(1-pyrrolidinyl)-
methyl]-lH-1,2,4-triazole-3-carboxamide;
~rom 28.4 g (0.06 mole) of 1-[2-(o-chlorobenzoyl)-4-
chlorophenyl]-5-(piperidinomethyl)-lH-1,2,4-triazole-3-
carboxylic acid methyl ester there is obtained 1-[2-(o-
chlorobenzoyl)-4-chlorophenyl]-5-(piperidinomethyl)-lH-
. 1,2,4-triazole-3-carboxamide; and
A 20 from 27.7 g (0.06 mole) of 1-l2-1chlorobenzoyl)-4-chlorophenyl]-
5-[(diethylarnino)-methyl]-lH-1,2,4~triazole-3-carboxylic
acid methyl ester there is obtained l-L2-(o-chloro~enzoyl)-4-
chlorophenyL]-5-[(diethylamino)-methy~ 2~4-triazole-3
carboxamide.
, . :. , ' . .' :: ., .'. , , ., . :
1074313
Example 16
With the use of a solution of 20 g (about 0.65 mole)
o methylamine in 120 ml of methanol, inste~d of the
ammonia solution, there is obtained, with the procedure
otherwise being analogous to that described in Example 15,
N-methyl-1-12-(o-chlorobenzoyl)-4-chlorophenyl]-5-
~morpholinomethyl)-lH-1,2,4-triazole-3-carboxamide.
There are obtained likewise analogously, starting
with the given amounts of the further three methyl esters
mentioned in Example 15:
N-methyl-1-[2-~o-chlorobenzoyl)-4-chlorophenyl]-5-l(l-
pyrrolidinyl)-methyl] l~-1,2,4-triazole-3-carboxamide;
N-methyl-1-l2-(o-chlorobenzoyl)-4-chlorophenyl]-5-
(piperidinomethyl)-lH-1,2,4-~riazole-3-carboxamide; and
N-methyl-1-(2-(o-chlorobenzoyl)-4-chlorophenyl]-5-l(dietnyl-
amino)-methyll-lH-1,2,4-triazole-3-carboxamide.
- 78 -
~ .: ,: ,. . .
. . .
- , :
: , . : -
1~1174313
Example 17
8.66 g (0.020 mole) of 1-[2-(o-chlorobenzoyl)-4-chloro-
phenyl)-5-l(dimethylamino)-methyl]-lH-1,2,4-triazole-3-
carboxylic acid methyl ester is co~7ered over with
400 ml of methanol and 80 ml of concentrated aqueous
S ammonia solution. The reaction solution is stirred for
16 hours at room temperature, and thereupon concentrated
in vacuo to dryness. Water is added to the residue and
extraction is performed twice with methylene chloride.
The organic phase is washed twice with ice-cold lN
sodium hydroYide solution and is then extracted twice
with 2N hydrochloric acid solution. To the aqueous
acidified solutions there are added ice and sufficient
SN sodium hydroxide solution to bring the pH-value to 10.
The precipitated base is taken up in methylene chloride.
The or~anic phase is washed twice with water and once with
saturated sodium chloride solution; it is dried over
sodium sulphate and concentrated by evaporation to dryness.
The amorphous residue is triturated with ether, whereupon
the reaction product precipitates in crystalline form. It
is filtered off with suction and washed with ether. After
drying, there is obtained l-[2-(o-chlorobenzoyl)-4-chloro-
phenyl]-5-~(dimethylamino)-methyl]-lH-l~2)4-triazole-3-
.. . . ... ,, - - -
, ,~ :, . .: .. ....
.. : :-. ... ;. .
- , ,.. ;., : ;.. . - . ~ ,,
. . . -.
:. . : .: ,. : . .
1074313
carboxamide, m.p. 177-180.
There is obtained in an analogous manner, with the
use o~ 6.5 g (0.21 mole) of methylamine in 40 ml of
me~hanol instead of the concentrated aqueous ammonia
S solution, N-methyl-1-[2-(o-chlorobenzoyl)-4-chlorophenyl]-
5-[(dimethylamino)-methyl~-lH-1,2,4-triazole-3-
carboxamide.
- ~0 -
- - ,. , : -
,~ : , , -, : ,
-, .
. ,, . , - :,
1074313
Example 18
A mixture of 8.0 g (0.015 mole) of 1-[2-(o-chloro-
benzoyl)-4-chlorophenyl]-5-(iodomethyl)-lH-1,2,4-
triazole-3-carboxylic acid methyl ester lsee Example 13 b)]
and 3.3 ml of l-methyl-piperazine in 160 ml of methanol
is stirred for 16 hours at 40. The reaction solution
is then concentrated in vacuo; water is added to the
residue and extraction is performed twice w;th methylene
chloride. The organic phase is washed ~ice with ice water,
and extraction is then performed twice with 2N hydrochloric
acid solution. To the aqueous acidified extracts there
are added ice and sufficient 5N sodium hydroxide solution
to bring the pH-value to 10. The base that has precipitated
is taken up in ether. The organic phase is washed twice
, wi.th saturated sodium chloride solution; it is afterwards
dried over 80dium sulphate and concentrated in vacuo to
dryness. There is obtained 1-[2-(o-chlorobenzoyl)-4-
chlorophenyl]-5-[(4-methyl-1-piperazinyl)-methyl]-lH-
1,2,4-triazole-3-carboxylic acid methyl ester as
solidiied foam.
The a~ove crude product is covered over with ~80 ml
of methanol and 56 ml o~ concentrated aqueous ammonia
solution. The reaction solution is stirred for about 15
- 8~ -
: - ,
: . : - , . ,.:
10743~3
hours at room temperature and is thereupon concentrated
in vaeuo. Water is added to the residue and extraction
is performed twice with methylene chloride. The organic
extracts are washed twice with ice-cold lN sodium
hydroxide solution, twice with water and once with
saturated sodium chloride solution; they are dried over
sodium sulphate and concentrated in vacuo to dryness.
The residue is recrystallised from isopropanol. After
drying, there is obtained 1-[2-(o-ehlorobenzoyl)-4-
ehlorophenyl]-5 L (4-methyl-1-piperazinyl)-methyl]-lH-
1,2,4-triazole-3-carboxamide, m.p. 167-169.
- 82 -
.. ... .
,. ~ -
:. , - ; -: ,. . . :, .,
., . - . .; .,
1074313
Example 19
2.50 ml (corresponding to 0.0067 mole of chromium
trioxide) of an oxidation solution according to Jones
(preparation of 250 ml by dissolving of 66.8 g of
chromium trioxide in 57.5 ml of concentrated sulphuric
S acid and making up with water to 250 ml) is added
dropwise at room temperature, with stirring, to a
solution of 4.22 g (0.01 mole) of 1-[2-(~-hydroxybenzyl)-
4-chlorophenyl]-5-[(dimethylamino)-methyl]-lH-1,2,4-
triazole-3-carboxamide-hydrochloride in 800 ml of acetone.
The reaction mixture, gradually assuming a green colour,
is stirred for 18 hours at room temperature, and then
concentrated in vacuo to 100 ml. Ice and saturated sodium
carbonate solution are added until the pH-value has reached
10, and extraction is performed twice with ethyl acetate.
The organic phase is washed twice with water and once with
saturated sodi~ chloride solution and dried over magnesium
sulphate. The drying agent is filtered off, and there is
added to the filtrate ethereal hydrogen chloride solution
until the pH-value has reached 3. The hydrochloride,
precipitating in crystalline form, is filtered off with
suction and washed with ethyl acetate and ether. After
drying in vacuo, there is obtained l-(2-benzoyl-4-chloro-
,~ ,.
... . ..
. . -, .:
.
,; , ... .
.
1074313
phenyl)-5-[(dimethylamino)-methyl]-lH-1,2,4-triazole-3-
carboxamide-hydrochloride, m.p. 250 (with decomposition).
The starting material is produced as follows:
a) 0.57 g (0.015 mole) of sodium borohydride is added
S all at once at 0, with stirring, to the solution of
5.6 g (0.015 mole) of 1-(2-benzoyl-4-chlorophenyl)-5-
(chloromethyl)-lH-1,2,4-triazole-3-carboxamide Isee
Example la)] in 250 ml of tetrahydrofuran and 25 ml of
methanol, and the whole is subsequently stirred for a further
hour at room temperature. There is then slowly added
dropwise, with ice-water cooling, lN hydrochloric acid
solution until ~he pH-value of the reaction mixture has
reached 4. The mixture obtained is concentrated in vacuo
to dry~ess. Water is added to the residue, and extraction
is perormed t~ice with ethyl acetate. The organic phase
is wash~d once with saturated potassium bicarbonate
solution, twice with water and once with saturated sodium
chloride solution; it is dried over sodium sulphate and
concentrated in vacuo. There is obtained amorphous 1-¦2-
(~-hydroxybenzyl)-4-chlorophenyl~-5-(chloromethyl)-1~-
1,2,4-triazole-3-carboxamide, which can be used directly
in the next stage. On the silica gel plate, the compound
has an Rf value of 0.61 in the system ethyl acetate/methanol
- 84 -
(95:5)-
. . , , ~ , ,
: , - . ... : : . ..
1074313
b) 6.8 ml of 33~/~ ethanolic dimethylamine solution is
added to a solution of 5.6 g (about 0.015 mole) of
1-[2-(a-hydroxybenzyl)-4-chlorophenyl]-5-(chloromethyl)-
lH-1,2,4-triazole-3-carboxamide and 0.225 g of sodium
iodide in 80 ml of methanol, and the whole is refluxed
for 5 hours with stirring. The reaction mixture is
thereupon concentrated in vacuo. Water and saturated sodium
carbonate solution are added to the residue until the
pH-value has reached 10, and extraction is performed
twice with ethyl acetate. The organic phase is washed
with water, and is then extracted three times with lN
hydrochloric acid solution. Sodium carbonate is added
to the aqueous acidified extracts until the pH-value of
10 is obtained. The base that has precipitated is taken
up in ether; the ether solution is washed twice with
water and once with saturated sodium chloride solution;
it is dried over sodium sulphate and concentrated in
vacuo to yield amorphous l-12-(a-hydroxybenzyl)-4-chloro-
phenyl]-5-~(dimethylamino)-methyl]-lH-1,2,4-triazole-3-
carboxamide. This is converted as follows into thecrystalline hydrochloride: the crude base ls dissolved
in ethyl acetate, and ethereal hydrogen chloride solution
- - 85 -
. , . . ;. .- ~
.. - . .
t . ..
- ; ~ .,...... ~ . -
1074313
is added until the pH-value is 4. The precipitated
hydrochloride is filtered off with suction and washed
with ethyl acetate and ether. After drying in vacuum,
there is obtained l-l2-(a-hydroxybenzyl)-4-chlorophenyl]-
5-[(dimethylamino)-methyl]-lH-1,2,4-triazole-3-
carboxamide-hydrochloride, m.p. 15~-157 (with
decomposition).
- 86 -
. , : '' '' '-` :,'
' ' '` " '`;
.' ' . ` ' ' ' ', . ' : ' ' "
- . '" ,-.~, ' ', ', _ ' ',
1074313
Example 20
The crude [l-l2-(a-hydroxybenzyl)-4-chlorophenyl]-5-
I(dimethylamino)-methyl]-lH-1,2,4-triazol-3-yl]-methyl]-
acetate (about 0.028 mole), obtained according to b)
lsee below], is dissolved in 1500 ml of acetone, and there
is then added dropwise to the solution at room temperature
in the course of 30 minutes, with stirring, 7.20 ml
(corresponding to 0.019 mole of chromium trioxide) of an
oxidation solution according to Jones which is prepared
by dissolving 66.8 g of chromium trioxide in 57.5 ml of
concentrated sulphuric acid and making up with water to
250 ml. The colour of the reaction mixture changes from
the initial yellow via reddish brown to a deep dark green.
After completion of the dropwise addition, the reaction
mixture is stirred for one hour at room temperature, and is
thereupon concentrated in vacuo at 30 to the extent of 50%.
There are then added ice and saturated potassium bicarbonate
solution until the pH-value reaches 8, and extraction is
perormed twice with ethyl acetate. The combined organic
phases are extracted twice with 2N hydrochloric acid
solution. There are added to the aqueous ac~dified extracts
ice and sufficient potassium carbonate to bring the pH-
value to 8. The precipitated base is ta~en up in ethyl
..... . ~ ,
.. . .
1~74313
acetate. The organic phase is washed twice with water
and once with saturated sodium chloride solution; it is
dried over sodium sulphate and concentrated in vacuo to
dryness. There is obtained crude [11-(2-benzoyl-4-
chlorophenyl)-5-l(dimethylamino)-methyl]-lH-1,2,4-
triazol-3-yl~-methyl]-acetate in the form of a
slightly yellow oil.
A specimen of the crude product is dissolved in
ether, and ethereal hydrogen chloride solution is added
until the pH-value is 3. The hydrochloride, obtained in
crystalline form, is filtered off with suction and, after
drying, has a melting point of 166-170.
The starting material is produced as follows:
a) ~.1 g (0.24 mole) o~ sodium borohydride is added
portionwise at room temperature, with stirring, to a
solution of 16.0 g (0.040 mole) of 1-(2-benzoyl-4-
chlorophenyl)-5-l(dimethylamino)-methyl]-lH-1,2~4-
triazole-3-carboxylic acid methyl ester lsee ~xample 2]
in 320 ml of tetrahydrofuran and 320 ml of methanol. The
temperature of the reaction solution rises during t'ne
addition to 40. The reaction mixture is subsequently
heated for one hour at 50; 100 ml of ice water is then
- 88 -
, - - . . . ~ . .. ;. . :
r,::
:' '' ' ' ' ,''":' ,'.': " ' .1.' . . .' ~' . , :
: .'. '.-' ' ''.. '' . :' ' : ' '
1074313
added, and the bulk of the tetrahydrofuran and of the
methanol is evaporated off in vacuo. The aqueous residue
is extracted twice with ethyl acetate. The organic phase
is washed once with lN sodium hydroxide solution, and
is then extracted three times with 2N hydrochloric acid
solution. Sodium carbonate is added to the a~ueous
acidified extracts until the pH-value reaches 10. The
precipitated base is dissolved in ethyl acetate; the
solution is washed twice with water and once with saturated
sodium chloride solution; it is dried over sodium
sulphate and concentrated in vacuo. The residue is triturated
with ether and hexane, whereupon the reaction product
precipitates in crystalline form. After filtration with
8uction and drying in vacuum, there is obtained 1-[2-
(~-hydroxybenzyl)-4-chlorophenyl]-5-[(dimethylamino)-
methyll-lH-1,2,4-~riazole-3-methanol, m.p. 121-123.
b) A solution of 3.0 ml (0.0318 mole) of acetic anhydride
in 5 ml o methylene chloride is addcd dropwise at 0
within 10 minutes to the solution of 11.18 g (0.030 mole)
of 1-12-(a-hydroxybenzyl)-4-chlorophenyl]-5-[(dimethyl-
amino)-methyl]-lH-l~2~4-triazole-3-methanol in 80 ml of
methylene chloride and 10 ml of pyridine, and the whole
is stirred for 20 hours at room temperature. There is
- 89 -
- . ,~ '~ '' '' '. -
- ,, , ; .. :- ,
.~
- , ., -, ...
1~743~3
then added a further 1.1 ml (0.012 mole) of acetic
anhydride, and stirring is maintained for 4 hours at
room temperature. The reaction mixture is concentrated
in vacuo, and the residue is concentrated to dryness
S twice with toluene. The amorphous residue is dissolved
in ethyl acetate, and the organic phase is washed twice
with water and once with saturated sodium chloride
solution. After drying over sodium sulphate and
concentration in vacuo, there is obtained amorphous ll-[2-
(~-hydroxybenzyl)-4-chlorophenyl]-5-l(dimethylamino)-
methyl]-lH-1,2,4-triazol-3-yl]-methyl]-acetate, which
can be used directly in the next step. To determine
characteristic properties, a specimen of the crude
product is dissolved in acetone, and a saturated solution
of oxalic acid in acetone is added until the pH-value of
3 is reached. The oxalate, which has crystallised out,
is filtered off with suction, and recrystallised from
hot acetone. After drying, the oxalate melts at 185-186
with decomposition.
Example 21
60 ml of lN sodium hydroxide solution (0.060 mole) is
added at room temperature, with stirring, to a solution of
- 90 -
,.~.. . .... . .. ..
lV74313
g.26 g (about 0.020 mole) of crude [~1-(2-benzoyl-4-
chlorophenyl)-5-[(dimethylamino)-methyl]-lH-1,2,4-
triazol-3-yl]-methyl]-acetate (see Example 20) in
250 ml of methanol and 115 ml of water. The temperature
of the reaction solution rises to 33. The reaction
mixture is stirred for one hour at room temperature,
and is subsequently concentrated in vacuo. Water is
added to the residue, and extraction is performed t-~!ice
with ethyl acetate. The combined organic phases are
extracted three times with 2N hydrochloric acid. There
are added to the aqueous acidified extracts ice and
sufficient sodium carbonate to bring the p~-value to 10.
The precipitated base is taken up in ethyl acetate. The
organic phase is washed twice with water and once with
saturated sodium chloride solution; it is dried over
sodi-~ sulphate and concentrated in vacuo. There is obtained
crude 1-(2-ben~oyl-4-chlorophenyl)-5-l(dime~hylamino)-
methyl]-lH-1,2,4-triazole-3-methanol as solidified foam.
A specimen of the crude product is dissolved in etller,
and ethereal hydrogen chloride solution is added until
the pH-value is 3. The hydrochloride, obtained in
crystalline form, is filtered off with suction and, after
drying, melts at 198-200 with decomposition.
- 91 -
, ,
, - . .. ..
. .
10743~3
Example 22
2.63 ml (corresponding to 0.007 mole of chromium
trioxide) of the oxidation solution according to Jones
[see Example 20] is added dropwise at 0 to 5, with stirring, to
a solution of 3.0 g (0.008 mole) of crude 1-(2-benzoyl-4-
chlorophenyl)-5-l(dimethylamino)-methyl~-lH-1,2,4-
triazole-3-methanol (see Example 21) in 670 ml of acetone.
The reaction mixture, which assumes after some ~ime a
deep green colour, is stirred for 2 hours at room temperature,
and afterwards concentrated in vacuo to the extent of 50%.
lQ There are then added ice and saturated sodium carbonate
solution until the pH-value of 9 is obtained, and
extraction is performed twice with ethyl acetate. The
combined organic phases are washed twice with water and
once with saturated sodium chloride solution; they are
dried over sodium sulphate and concentrated in vacuo to
dryness. The residue is dissolved in ethyl acetate/isopropanol
(4:1), and the solution is chromatographed on a column of
200 g of silica gel. The eluant used is ethyl aceta~e/
isopropanol (4:1). The fractions which contain the desired
aldehyde are combined and concentrated by evaporation.
There is obtained crude 1-(2-benzoyl-4-chlorophenyl)-5-
I(dimethylamino)-methyll-lH-l~2~4-triazole-3-carboxaldehyde
:.
,:,.: ~ ~ . : ., .. :
, ~ : , , . .. : , .:
- : : : ; - :. .: -
.. ... . . ..
1074313
as solidified foam.
A specimen of the aldehyde is dissolved in acetone,
and a saturated solution of oxalic acid in acetone is
added until the pH-value is 3. The oxalate precipitates
S in crystalline form. It is filtered off with suction,
washed well with acetone and ether and dried in vacuo;
m.p. 178-181 with foaming.
Example 23
5.1 ml (corresponding to 0.0136 mole of chromium
trioxide) of the oxidation solution according to Jones
(see Example 20) is added dropwise at 0, with stirring,
to a solution of 3.79 g (0.001 mole) of 1-12-(a-hydroxy-
benzyl)-4-chlorophenyl~-5-l(dimethylamino)-methyl]-3-
methanol in 740 ml of acetone, and the whole, after
completio~ of the dropwise addition, is stirred for a
further 30 minutes at room temperature. The green reaction
mixture is thereupon concentrated in vacuo to half its
amount; ice water and saturated sodium carbonate solution
are added until the p~-value reaches 9, and extraction is
performed twice with ethyl acetate. The combined organic
phases are washed twice with water and once with saturated
sodium chloride solution; they are dried over sodium sulphate
- 93 -
: ~ . ~ . .. . .
, i . . . . . . .. . . . .
. .- . ~ . , -.
.
1074313
and concentrated in vacuo. The amorphous residue is
dissolved in ethyl acetate/isopropanol (4:1), and the
solution is chromatographed on a column of 250 g of
silica gel. The eluant used is ethyl acetate/isopropanol
(4:1). The fractions which contain the desired aldehyde
are combined and concentrated by evaporation. The residue
is dissolved in acetone, and a saturated solution of
oxalic acid in acetone is added until the pH-value is 3.
The oxalate, obtained in crystalline form, is filtered
off with suction, and washed with acetone and ether.
After drying, there is obtained 1-(2-benzoyl-4-chlorophenyl)-
5-[(dimethylamino)-methyll-lH-1,2,4-triazole-3-carboxaldehyde-
oxalate, m.p. 178-181 with foaming.
Example 24
- ~ solut~on of 0.78 ml (0.01 mole) of methanesulphonic
acid chloride in 8 ~1 of anhydrous methylene chloride is
added dropwise at 0, with stirring, to the solution of
2.0 g (0.005 mole) of crude 1-(2-benzoyl-4-chlorophenyl)-5-
~(dimethylamino)-methyll-1~-1,2,4-triazole-3-methanol in
66 ml of anhydrous methylene chloride and 1.33 ml of
triethylamine, and the whole is stirred, without further
cooling, for one hour. Ice water and 120 ml of methylene
- 94 -
.
.- . . . , -
~ . . ~ . ..
. ~ . ,: . - ,
10743'13
chloride are added to the reaction mixture; the aqueous
phase is separated, and the organic phase is washed twice
with ice-cold potassium bicarbonate solution and twice
eh/0~ c
with saturated sodiumlsolution. After drying over
magnesium sulphate and removal of the solvent by
evaporation in vacuo, there remains the crude methane
sulphonic acid ester of the starting material.
The crude methanesulphonic acid ester obtained above
i8 dissolved in a mixture of 4.6 ml (0.03 mole) of 30%
ethanolic dimethylamine solution and 60 ml of methanol,
and the solution is allowed to stand for 16 hours. The
reaction mixture is then evaporated in vacuo to dryness;
there are added to the residue ice water and su~ficient
saturated sodium carbonate solution to bring the pH-value
to 10; and extraction is performed three times with ethyl
flce~ate. The organic phase is washed once with water, and
iB thereupon extracted three times with 2N hydrochloric
acid. Sodium carbonate is added to the acidified aqueous
extracts until the pH-value is 10, and extraction is then
performed twice with ethyl acetate. The combined ethyl
acetate solutions are washed twice with water and once with
saturated sodium chloride solution; they are dried over
magnesium sulphate and filtered. There is added to the
- ~5 -
~ '~ ' , , . ~ . .
1074313
filtrate sufficient ethereal hydrogen chloride solution
to bring the pH-value to 3. The product, precipitating
in crystalline form, is filtered off with suction, and
thoroughly washed with ethyl acetate and ether. After
S drying in vacuo, there is obtained 1-(2-benzoyl-4-
chlorophenyl)-3,5-bis-l(dimethylamino)-methyl~-lH-
1,2,4-triazole-dihydrochloride, m.p. 90 (with
gradual decomposition).
- 96 -
~ ,. . ...... ... .. . .
- .. .
1~74313
Example 25
A mixture of 4.18 g (0.01 mole) of 1-[2-(o-chloro-
benzoyl)-4-chlorophenyl]-5-~(dimethylamino)-methyl]-lH-
1,2,4-triazole-3-carboxamide and 2.86 g (0.015 mole) of
p-toluenesulphonic acid chloride in 2.42 ml of pyridine
and 24 ml of N,N-dimethylformamide is stirred for 2
hours at room temperature. The initially yellow colour
of the reaction mixture changes during this time to
green and then to red-brown. The reaction solution is
poured into ice water, and extraction is performed twice
with ether. The organic phase is washed three times with
water and once with saturated sodium chloride solution;
it is dried over sodium sulphate and concentrated in
vacuo to dryness. The residue is crystallised from isopropanol.
After filtration with suction followed by drying, there
i8 obt~ined 1-12-(o-chlorobenzoyl)-4-chIorophenyl3-5-
l(dimethylamin~)-methyll-lH-1,2,4-triazole-3-carbonitrile,
m.p. 117-119.
There is obtained analogously,
from 3.84 g (0.01 mole) of 1-(2-benzoyl-4-chlorophenyl)-5-
l(dimethylamino)-methyl~-lH-l~2~4-triazole-3-carboxamide~
amorphous l-(2-benzoyl-4-chlorophenyl)-5-~(dimethylamino)-
methyll-lH-1,2,4-triazole-3-carbonitrile. An addition is
- 97 -
.
.,, , : . . .
1~74313
made to this compound in etheral solution of a solution
o hydrogen chloride in ether, whereupon the crystalline
h~drochloride precipitates; it is filtered with suction
and washed with ether and hexane. After drying, the
resulting 1-(2-benzoyl-4-chlorophenyl)-5-l(dimethylamino)-
methyl]-lH-1,2,4-triazole-3-carbonitrile-hydrochloride
melts at 216-219 with decomposition.
Example 26
150 ml of isopropanol is saturated at 0 with ammonia
gas. To this solution there are added at 0, with stirring,
2.45 g (0.05 mole) of sodium cyanide and, after 5 minutes,
a solution of 3.69 g (0.01 mole) of crude 1-(2-benzoyl-4-
chlorophenyl)-5-l(dimethylamino)-methyl]-lH-1,2,4-triazole-
3-carboxaldehyde in 30 ml of isopropanol. There are
then added at 0, at intervals of 10 minutes, 2 portions
each of 8.70 g (0.10 mole) of manganese dioxide, and the
reaction mixture is stirred for 4 hours at 0.
The reaction mixture is thereupon diluted with 250 ml
of methylene chloride, and the whole is filtered through
diatomaceous earth. The clear filtrate is concentrated
in vacuo to dryness. The residue is dissolved in ethyl
acetate/methanol (4:1), and the solution is chromatographed
- 98 -
t ' ' '
1~74313
on a column of 300 g of silica gel. The eluant used is
cthyl acetate/methanol (4:1). The fractions which
contain the desired product are combined and concentrated
by evaporation. The amorphous residue is dissolved in
50 ml of ethyl acetate, and ethereal hydrogen chloride
solution is added until an acid reaction to Congo red
is indicated. The hydrochloride, obtained in crystalline
; form, is filtered off with suction and washed with
ethyl acetate and ether. After drying, the resulting
1-(2-benzoyl-4-chlorophenyl)-S-[(dimethylamino)-methyl]-
; lH-1,2,4-triazole-3-carboxamide-hydrochloride melts at
250 with decomposition.
The aldehyde required as starting material can be
produced according to Example 22 or 23.
_ 99 _
.;
, .,~ . . . .
1~743~3
Example 27
40 ml of lN sodium hydroxide solution is added to
the solution of 5.37 g (0.01 mole) of crude [2-(dimethyl-
amino)-acetamido-[2-(o-chlorobenzoyl)-4-chlorophenylazo]-
malonic acid diethyl ester in 60 ml of methanol, and
the reaction mixture is heated, with stirring, for 3
hours at 50. The methanol is thereupon evaporated off
in vacuo, the residue is diluted with ~0 ml of water
and 1 g of active charcoal is added. After filtration
through purified diatomaceous earth, there is added to
the clear filtrate 2N hydrochloric acid solution until
the pH-value is 7, and washing with methylene chloride is
performed. The aqueous phase is then concentrated to
dryness in vacuo, and the residue, to effect complete
drying, i8 concentrated twice with methanol/toluene (1:1)
in vacuo at 40. The residue is sub~equently boiled out
with methanol. The undissolved inorganic salts are
~eparated off by filtration through purified diatomaceous
earth, and the clear filtrate is concentrated by evaporation
to dryness. The residue consists of pure 1-[2-(o-chloro-
benzoyl)-4-chlorophenyll-5-[(dimethylamino)-methyl]-lH-
1,2,4-triazole-3-carboxylic acid, which optionally can
be used directly for the next step, the convergion into
- 100 -
,', ' ": ,, ' ' , , ' '; '
~: " :,' ' . : : .
' ' " , ~ ~ '
1~74313
the methyl ester serving for its part, e.g., as r
8tarting material for Example 15.
For conversion into the hydrochloride, a saturated
solution of hydrogen chlorlde in ether is added to a
specimen of the carboxylic acid in ethanol until the
pH-value of the mixture, after the addition of water,
is 3. After the addition of ethyl acetate, the salt
crystallises out. It is filtered off with æuction and
washed with ethyl acetate and hexane. After drying, the
resulting 1-[2-(o-chlorobenzoyl)-4-chlorophenyl]-5-
(dimethylamino-methyl)-lH-l,2,4-triazole-3-carboxylic
acid-hydrochloride melts at 220 with decomposition.
For conversion into the methyl ester already mentioned,
10 ml of a 6N solution of hydrogen chloride in methanol
is added to a solution of 2.08 g (0.005 mole) of crude
1-[2-(o-chlorobenzoyl)-4-chlorophenyl]-5-(dimethylamino-
methyl)-lH-1,2,4-triazole-3-carboxylic acid in 30 ml of
methanol, and the whole is refluxed for 16 hours. The
reaction mixture is thereupon concentrated in vacuo.
20 Water is added to the residue, and extraction is performed
twice with methylene chloride. The organic phase is washed
twice with ice-cold lN sodium bicarbonate solution and twice
with saturated sodium chloride solution; it is dried over
- 101 -
. .
- , . .:..... . . .
. - . . .
lQ74313
sodium sulphate and concentrated in vacuo. The residue
crystallises out on trituration with ether. After
filtration with suction and drying in vacuo, there is
obtained pure 1-12-(o-chlorobenzoyl)-4-chlorophenyl]-5-
(dimethylamino-methyl)-lH-1,2,4-triazole-3-carboxylic
acid methyl ester, m.p. 133-135.
The starting material for the first step (ring
closure) is produced as follows:
a) A solution of 5.02 g (0.02 mole) of (2-chloroacetamido)-
malonic acid diethyl e~ter [see Ajay Kumar Bose, J.Indian
Chem. Soc. 31, 108-110 (1954)] and 4.50 g (().03 mole)
of sodium iodide in 100 ml of acetone is refluxed for
30 minutes. The reaction mixture is thereupon concentrated
in vacuo. Water is added to the residue, and extraction
lS i8 performed twice with methylene chloride. The organic
pha8e i8 washed once with diluted aqueou~ sodium bisulphite
~olution and twice with saturated sodium chloride solution;
it is dried over sodium sulphate and concentrated in vacuo.
The residue i8 recrystallised from methylene chloride/
hexane. After filtration with suction and drying in vacuo,
there is obtained (2-iodoacetamido)-malonic acid diethyl
ester, m.p. 95-97.
b) A mixture of 5.16 g (0.015 mole) of (2-iodoacetamido)-
- 102 -
I . ' .
: . . . - . ,
... . ..
1074313
malonic acid diethyl ester and 8.0 ml (0.045 mole) of
33% ethanolic dimethylamine solution in 50 ml of
ethanol is stirred for 16 hours at room temperature.
The reaction solution is thereupon concentrated in
vacuo; water is added to the residue and extraction is
performed twice with ether. The organic phase is washed
twice with ice water and once with saturated sodium
chloride solution; it is dried over sodium sulphate
and concentrated in vacuo. The residue, a viscous oil, is
practically pure 12-(dimethylamino)-acetamido]-malonic acid
diethyl ester, and is used directly for the next step.
c) A solution of 4.53 g (0.017 mole) of 2-amino-2',5-
dichloro-benzophenone lsee ~.H. Sternbach et al., J.Org.
Chem. 26, 4448 (1961)] in 21 ml of glacial acetic acid/
conc. hydrochloric acid (4:1) is diazotised at room
temperature, with stirring, with 3.4 ml (0.014 mole) of
5-molar aqueous sodium nitrite solution. The diazonium
salt solution obtained is cooled to 10j 9 g of ice is
added thereto and there is then quickly added dropwise
a solution of 4.43 g (0.017 mole) of crude 12-(dimethyl-
amino)-acetamido]-malonic acid diethyl ester in 44 ml of
acetone. There is su~sequently added dropwise at 5-10,
within 15 minutes, a saturated aqueous potassium car~onate
- 103 -
1074313
solution until the pH-value is 6. Stirring is maintained
for a further hour at room temperature, and 150 ml of
ether is then added. The ether layer is separated, and
washed twice with ice water and once with saturated
sodium chloride solution; it is dried over sodium
sulphate and concentrated in vacuo. The residue, a
yellow-brown oil, consists of practically pure [2-
(dimethylamino) acetam~do~-12-(o-chlorobenzoyl)-4-
chlorophenylazo]-malonic acid diethyl ester. The
compound shows on silica gel thin-layer plates an
Rf-value of 0.36 in the system toluene/ethyl acetate (1:1).
- 104 -
:
, ~ .
1074313
Example 28
A solution of 5.37 g (0.01 mole) of crude [2-(dimethyl-
~mino)-acetamidol-[2-(o-chlorobenzoyl)-4-chloro-
phenylazo]-malonic acid diethyl ester lsee Example 27 a)
to c)] and 50 ml of conc. aqueous ammonia solution in
S 100 ml of methanol is stirred for 16 hours at room
temperature. The reaction mixture is thereupon concentrated
in vacuo. Water is added to the residue and extraction
i8 performed twice with methylene chloride. The organic
phase i8 extracted twice with ice-cold lN hydrochloric
acid. To the acid aqueous extraction there is added 5N
sodium hydroxide solution until the pH-value has reached
11; and the formed dispersion of the reaction product is
extracted twice with methylene chloride. The organic
phase is washed twice with water and once with saturated
80dium chloride solution; it is dried over sodium sulphate
and concentrated in vacuo to dryness. The residue
crystallises out on trituration with ether. After
filtration with suction and drying in vacuo, there is
obtained, as a result of decarbethoxylation, ring closure
and ammonolysis of the ester group remaining, performed
in the same operation, 1-12-(o-chlorobenzoyl)-4-chlorophenyl]-
5-l(dimethylamino)-methyl)-lH-1,2,4-triazole-3-carboxamide,
m.p. 178-180~. - 105 -
