Note: Descriptions are shown in the official language in which they were submitted.
f ~ P.C.(Ph) 6483A/6554A
[1,2,4]TRIAZOLO[4,3-a]QUINOXALINE~4-AMINE DERIVATIVES
This invention relates to a series of novel [1,2,4~
triazolo[4,3-a]quinoxaline-4 amine derivatives and their pharma-
ceutically acceptable acid addition salts which are useful as
antidepressant and antifatigue agents.
An intensive search has heen undertaken for agen-ts
which are effective in reducing the symptoms of depression and
fatigue in mammals.
U.S. Patent No. 3,839,569 and West German Patent No.
2,249,350 respectively disclose the use of s-triazolo[4,3-a]
quinolines and lH-imidazo[4,5-b]quinoxalines as agrlcultural
fungicides. U.S. Patent No. 4,008,322 discloses the use of a
series of triazolo[4,3-a]quinoxaline derivatives for control of
rice blast caused by the phytopathogen Piricularia oryzae.
The present invention relates to novel [1,2,4]-
trlazolo[4,3-a]quinoxaline-4-amine derivatives useful as anti-
depressant and anti-fatigue agents.
Specifically, the compounds of the present invention
are of the formula:
~ i
~2
R~
~G
X > ~ ~N ~ NR2R3
and the pharmaceutically acceptable acid addition salts
thereof, wherein
X and Xl are each selected from the group consîsting
of hydrogen, fluorine, chlorine, bromine and me~hoxy;
Rl is selected from the group consisting of hydrogen,
lower alkyl, lower perfluoroalkyl and phenyl; and
R~ and R3 are each selected from the group consisting
of hydrogen, lower alkyl, phenylalkyl having up to three
carbon a~oms in the alkyl moiety and alkanoyl having from
two to five carbon atoms, provided that at least one of R2
and R3 is always other than hydrogen when X and Xl are each
hydrogen and Rl is hydrogen or methyl; or R2 and R3, when
taken ~ogether, comple~e a piperazino ring.
For purposes of the presen~ specification and claims,
by lower alkyl is meant alkyl having 1 to 4 carbon atoms
and by lower perfluoroalkyl is meant perfluoroalkyl having
from 1 to 4 carbon atoms like trifluoromethyl and
pentafluoroethyl, etc.
One group of compounds of interest are those wherein
X and Xl are each hydrogen, Rl is hydrogen, and R2 and
R3 are each lower alkyl. Preferred compounds include
those wherein R2 and R3 are both ethyl.
Another group of compounds of the presPnt invention are
those wherein X and Xl are each hydrogen, Rl is e~hyl and R3
is lower alkyl. Preferred compounds are those wherein R2 is
hydrogen and R3 is ethyl.
Still another group of compounds of the present inven-
tion are those wherein X and Xl are each hydrogen, Rl is
lower alkyl and R3 is acetyl. Preferred compounds include
those wherein Rl is ethyl and R2 is hydrogen, ethyl or
acetyl.
A further group oE compounds of interest of the
present invention are those whereln at least one of X and Xl is
fluorine, Rl is hydrogen or trifluoromethyl, R2 i6 hydrogen and
R3 is hydrogen, lower alkyl or alkanoyl having from two to five
carbon atoms; or, alternatively, wherein at least one of X and
xl is chlorine, Rl is lower alkyl or trifluromethyll R2 is hydro-
gen and R3 is hydrogen, lower alkyl or alkanoyl having from two to
five carbon atoms.
Also embraced by the present invention are pharmac-
eutical compositions comprising an antidepressant, anti~atigueef~ective amount of a compound of Formula I or a pharmaceutically
acceptable acid addition salt thereof, together with a pharmac-
eutically acceptable carrier or diluent. Preferred pharmaceut-
ical compositions are those containing the preferred compound
of Formula I as described hereinabove.
The present invention also comprises a method of
treating depression and fatigue in a mammal in need of such
treatment, which comprises administering to said mammal an anti-
depressant/anti~atigue effective amount of a compound of formula
I or a pharmaceutically acceptable acid addition salt thereof.
Preferred compounds for use in this method of treatment are the
preferred compounds of formula I as described hereinabove.
The majority of the novel compounds of formula I may
be prepared by the reaction sequence shown in reaction scheme I.
The numbering of the phenyl and the two heterocyclic rings in
scheme I is that employed throughout the specification.
~;
~'
- 3a - ~ ?r~77z
In scheme I, a compound of formula IV, a quinoxaline
derivative wherein X and Xl are each hydrogen, fluorine,
chlorine, bromine or methoxy, with the proviso that X is always
hydrogen when said quinoxaline derivative is monosubstituted in
the benzene ring, is treated with an excess molar arnount of hyd-
razine hydrate in a polar, reaction-inert organic solvent such
as an alkanol having from 1 to 3 carbons, preferably ethanol,
at room temperature for a period of about 18-24 hours to form
an intermediate compound of formula III.
The intermediate compound of formula III may then
be subsequently converted ~o the corresponding inter-
mediate of formula IIA, wherein Rl i9 other than lower
perfluoroalkyl, by treatment with an appropriate alkyl
orthoalkanoate or alkyl orthobenzoate, as the case may
be, a~ a temperature between about 80 and 120C. for
about 1 to 24 hours. In the resulting compound of
formula IIA, Rl (as hydrogen or alkyl) is determined by
the particular orthoalkanoate employed in the synthesis.
Thus, for example, when triethyl orthoformate is used,
Rl is hydrogen, when triethyl orthopropionate i5 used,
Kl iS ethyl and when trie~hyl orthoisobutyrate is used,
Rl is isopropyl.
The in~ermediate compound of formula III may also be
converted to the corresponding intermediate of ~ormula IIA
wherein Rl is lower perfluoroalkyl by treatment with an
excess molar amount of an appropriate perfluoroalkanoic
acid, such as trifluoroace~ic acid or pentafluoropropionic
acid, e~c~, as ~he case may be, in a conventional manner to
yield the corresponding 4-hydroxy-1-perfluoroalkyl-[1,2,4]-
triazolo[4,3-a]quinoxaline, followed by treatment of the
latter type compound with phosphorus oxychloride in the
presence of a tertiary amine, such as triethylamine, at
elevated temperatures to yield the corresponding 4-chloro
compound.
Intermediate IIA (wherein Rl is hydrogen, lower alkyl,
lower perfluoroalkyl or phenyl~ is then converted to a
[1,2,4]triazolo~4,3-a]quinoxaline-4-amine derivative of
formula IA, wherein R2 and R3 are each as previously defined
e~cept that they are other than alkanoyl, by treatment with
an excess molar amount of an amine of the ~ormula HNR2R3
in a reaction-inert organic solvent, preferably N,N-dimethyl-
formamide, at a tempe~ature between about 0 and 60C. for
about 2 to 24 hours. For example, the preferred compounds of
formula IA in which R2 and R3 are both ethyl are prepared by
treating the appropriate compound of formula IIA with
diethylamine in N,N-dimethylformamide at room tempera-
ture for 2-3 hours, Likewise, preferred compounds of
~ ~n~~ ~r~
_5_ ~ ~r ~ ~ ~
formula IA wherein R2 is hydrogen and R3 is ethyl are pre-
pared by treating a compound of formula IIA with monoe~thylamine
in N,N-dimethylformamide at room tempera~ure for 4 to 5
hours.
[1,2,4]Triazolo[4,3-a~quinoxaline-4~amine derivatives of
the formula IA wherein at least one of R2 and R3 is alkanoyl
having from two to five carbon a~oms are prepared from the
corresponding compounds of formula IA where at least one of
R2 and R3 is hydrogen by contacting the latter with the
appropriate alkanoic acid anhydride under substantially
anhydrous condi~ions. This reaction can be carried out
in the presence of an organic base, such as a tertiary
amine, as catalyst (although this is not absolutely necessary)
at a temperature ranging from about 20C. up to about 140~C.
or a period of about one-half to about 24 hours. The
molar ratio of acid anhydride to the 4-amino starting
material should be at least about 1:1 and preferably from
about 4:1 to about 25:1, while the amount of tertiary
amine employed is normally about 25 to 150~ by weight of
the aforesaid acylating agent (the tertiary amine may be
used as the reaction solvent by merely employing an excess
of same). Although it is quite possible and even, in some
instances, highly desirable to carry out the reaction in
the absence of a solvent, there may be times when the use
of a suitable reaction-inert organic solvent is clearly
indicated. Suitable organic solvents for use in this
connection include neutral, reaction--inert anhydrous
organic solvents, such as acetone, methyl ethyl ketone,
benzene, toluene, xylene, dioxane, tetrahydrofuran, methylene
chloride, chloroiorm, ethylene dichloride, tetrachloroethane,
methyl acetate, ethyl acetate, isopropyl acetate, methyl
propionate, ethyl propionate, diethyl ether, diisopropyl
ether, di-n-propyl ether and the like. However, as
previously indicated, the reaction is ordinarily conducted
in the absence of such a solvent by merely employing an
excess of acid anhydride. Similarly, an excess of the tertiary
-6~
amine reagent may also serve as a solvent. Preerred tertiary
amines for use as solvents and/or as catalytic reagents in
this reaction include triethylamine, dimethylaniline, pyridine,
picoline, lutidine, collidine and quinoline.
The starting materials of formula IV wherein X and Xl
are each hydrogen are well known in the art. Compounds of
formula IV wherein Xl is methoxy may be prepared by the
method of G. W. H. Cheeseman [J. Chem. Soc., p. 1170 (1962)]
wherein 4-methoxy-o-phenylenediamine hydrochloride is
treated with at least an equimolar amoun~ of diethyl oxalate
and diethylamine under an atmosphere o~ inert gas,
preferably nitrogen, at reflux temperature for about 2 to 3
hours, followed by treatment with phosphorus oxychloride
in a tertiary amine, preferably dimethylaniline, at reflux
temperatures for 1-2 hours.
In reaction scheme II, a quinoxaline derivative of the
formula IV9 wherein X is fluorine, chlorine, bromine or
methoxy and Xl is hydrogen, is treated with sodium methoxide
in an alcoholic solvent medium at slightly elevated temp-
eratures (e.g., 40-60C.) for a period of approximately
6-18 hours to form the corresponding 2-chloro-3-methoxyquin-
oxaline derivative of formula V, which is then treated with
hydrazine hydrate in the same manner as before to yield the
corresponding 2-hydrazino-3-methoxyquinoxaline derivative
of formula VI. The latter intermediate (VI) is then sub-
sequently converted to the desired 7-substituted 4-methoxy-
[1,2,4]triazolo[4,3-a]quinoxaline derivative of formula VII
by use o an appropriate ortho ester, or with perfluoro-
alkanoic acid, in the same manner as previously described,
and ~he latter compound is then successively converted to
the corresponding 4-hydroxy (see formula VIII) and 4-chloro
compounds by conventional procedure to yield a compound of
structural formula IIB wherein X is as hereinbefore deined
above (i.e., other than hydrogen) and Xl is hydrogen. This
in~ermediate of formula IIB then leads to the corresponding
novel final products of formula IB, wherein Rl, R2 and R3
are all as previously de~ined and X and Xl are as above, by
z
-- 7
merely employing the reaction procedures previously descrlbed
in connection with the discussion o~ the last stages of
over-all scheme I.
The pharmaceutlcally acceptable acid addition salts of
the novel compounds of formula I are also embraced by the
present invention. These salts may be readily prepared by
contacting the ~ree base with an appropriate mineral or
organic acid in either aqueous solution or in a suitable
organic solvent. The solid salt nay then be obtained by
precipitation or by evaporation of the solvent. The pharma-
ceutically acceptable acid addition salts of this invention
include, but are not limited to, the hydrochloride, sulfate,
bisulfate, mesylate, tosylate, nitrate, phosphate, acetate,
lactate, maleate, ~umarate, citrate, tartrate, succinate,
1uconate and the like. Mesylate salts are preferred. If des-
ired, the compounds of formula I as the free base may he formed
from the acid addition salts thereof by treatment with an
appropriate base, followed by extraction of the free base with a
suitable organic solvent.
The compounds of formula I and the pharmaceutically
acceptable acid addition salts thereof have activity as anti-
depressant and anti-fatigue agents and accordinglyr are of
therapeutic value in the treatment of symptoms associat@d with
depressions and fatigue. The compounds may be administered to a
subject in need of treatment by a variety of conventional routes
of administration including orally and parenterally. Preferably,
' ~
'~,.
- 7a -
7~
the compounds are administered orally. In general, these com-
pounds will be administered orally at one or more doses between
about 0.1 to 100 mg/kg. body weight of the subject to be treated
per day, preferably from about 0.5 -to 10 mg./k per day. If
parenteral or intravenous administration is desired, then these
compounds can be given at doses between about 0.1 to 10 mg./kg.
body weight of the subject to be trea~ed per day. However, some
variation in dosage will necessarily occur depending upon the
condition of the subject being treated and the particular
compound employed.
~.
~ --8--
'YZ
REACTION SCHRMR I
-
X~ ~Cl
X ~N~Cl IV
X ~ NHNH2
~I~ ,~C 1 I I I
~1
Cl IIA
( Exc lude s X 1 =H; X7~H
I
R
xl ~
X~NR2R3 (Excludes Xl=H; X~H)
-8a~ 7 7 ~Z:
REACTION SCHEME II
X ~N~
~I~N~ Cl IV
X
X~ ~C 1 V
X~ ~NH2 VI
X
xl ~F~
~ ~N
X~ OCH3 VI I
~r3~ gd~
` -8b -
Xl ~
~OH VI I I
R~,~
'~
~ N IIB (X1=H; X~H)
~Cl
X
X ~ ~
3~ ~ IB ~Xl=H; X7~H)
X NR2R3
7 ~ 7 Z
The compounds may be administered alone or in
combination with pharmaceutically acceptable carriers
or diluents, in either single or multiple doses.
Suitable pharmaceutical carriers include inert diluents
or fillers, sterile aqueous solutions and various
organic solvents. The pharmaceutical compositions
formed by combining the novel compounds of Formula I
or salts thereof and pharmaceutically acceptable
carriers are readily administered in a variety of
dosage forms such as tablets, powders, capsules,
lozenges, syrups and the like. These pharmaceutical
compositions can, if desired, contain additional
ingredients such as flavorings, binders, excipients
and the like. Thus, for oral administration, tablets
containing various excipients, such as sodium citrate,
may be employed, together with various disintegrants
such as starch9 alginic acid and certain complex
silicates, together with binding agents such as
polyvinylpyrrolidone, sucrose, gelatin and acacia.
The activity of the compounds of the present
invention as antidepressan~ and anti-fatigue agents
is determined by various standard pharmacological tests,
including, for example, Porsolt's screening model of
"learned helplessness", i.e., immobility induced by
forced swimming in rats [R. D. Porsolt et al., European
J. Pharmacol., 47, 379 (1978)]. Pharmaceutical agents
of this type which are therapeutically effective in humans
are known to reduce immobility induced by forced swimming
in this model.
The present invention is illustrated by the
following e~amplesr However, it should be
understood that the invention is not limited to the
specific details of these e~amples. All temperatures
are in degrees centigrade.
-lo~ 7~
Preparation A
4-Chloro-7-fluoro-[1 t 2,4]triazolo[4,3-a]quinoxaline
a) Preparation of 2-chloro-6-fluoro-3-methoxyquinoxaline
In a flame-dried reaction 1ask containing a slurry
of 52 g. (0.24 mole) of 2,3-dichloro-6 fluoroquinoxaline
in 500 ml. of methanol under a dry nitrogen atrnosphere,
there was added slowly in a dropwise manner at 50C.
a solution consisting of 6.6 g. (0.29 mole) of sodium
dissolved in 650 ml. of methanol. The resulting reaction
mixture was then heated at 50C. overnight (i.e., for a
period of approximately 16 hours) and the clear solution
so obtained was allowed to cool to room temperature
~r320C.) The reaction mixture was then concentrated
_ vacuo, and the residual material susequently dissolved
in chloroform, washed with water and dried over anhydrous
magnesium sulfate. After removal of the drying agent by
means of filtration and the solvent by means of evaporation
under reduced pressure, there was ul~imat~ly obtained a
liquid residue that was subsequently chromatographed on
a 1000 ml. silica gel column, followed by elution with
toluene. The combined fractions containing only product
then gave 48.3 g. (95%) of pure 2-chloro-6 fluoro-3-
methoxyquinoxaline, m.p. 93-95C. Mass Spectrum:
m/e, 212(P); m/e, 214 (P+2).5 b~ Prepara~ion of 6-fluoro-2-hydrazino-3-methoxyquinoxaline
To a solution consisting of 47 g. (0.22 mole) of
2-chloro-6-fluoro-3-methoxyquinoxaline dissolved in 1000 ml.
of ethanol, there were added 27.6 g. (0.55 mole) of hydra-
zine hydrate t26.8 ml.). The resulting mixture was stirred
at room temperature overnight (i.e., at caO 20C. for ap-
proximately 16 hours~. An additional amount of hydrazine
hydrate (9.0 ml.) was then added and the final reaction
mixture was allowed to stlr at room temperature for a
period of four hours. At this point, the precipitate
was filtered and washed with ethanol to ultimately
afford 43.3 g. (94~).of pure 6--fluoro-2-hydrazino~3-
methoxyquinoxaline, m.p. 170-174C. (decomp.).
c) Preparation of 7-fluoro-4-methoxy-[1,2,4]triazolo-
[4,3-a]quinoxaline
A mixture consisting of 15 g. (0.072 mole) of
6-fluoro-2-hydrazino-3-methoxyquinoxaline and 250 ml. of
triethyl orthoformate was heated with mechanical stirring
in a preheated oil both at 100C. overnight ( ~16 hours).
The resulting mixture was then cooled to room temperature,
and the precipitate which formed was su~sequently re
covered by means of suction filtration and washed with
ethanol to ultimately afford 11.3 g (72%~ of pure 7-fluoro-
4-methoxy-[1,2,4]triazolo[4,3-a]quinoxaline, m.p. 245-
246C. (decomp.).
d) Preparation of 7-fluoro-4-hydroxy-[19 2,4]triazolo
C4,3-a]quinoxaline
A mixture consisting of 11.3 g (0.52 mole) of
7-fluoro-4-methoxy-[1,2,4]triazolo[4,3-a]quinoxaline,
115 ml. of lN hydrochloric acid and 345 ml. of glacial
acetic acid was refluxed for a period of three hours.
Upon completion of this -step, the reaction mixture was
cooled to room temperature and poured over ice/water.
The resulting mixture was then stirred for a period of
30 minutes and thereafter filtered to remove the pre-
cipitate, which was subsequently washed with water and
air-dried to ultimately afford 8.9 g. (84Z) of pure
7-fluoro-4-hydroxy-[1,2,4]triazolo[4,3-a]quinoxaline,
mOp.~300C. Mass Spectrum: m/e, 204 (P).
e) Preparation of 4-chloro-7-fluoro-[1,2,4]triazolo-
[4,3-a]quinoxaline
In a flame-dried reaction flask under a dry nitrogen
atmosphere, ~here were placed 8.9 g. (0,044 mole) of 7-
fluoro-4-hydroxy-[1,2,4]triazolo[4,3-a]quinoxaline and
160 ml. of phosphorus oxychloride together with 8.9 ml.
of tri n-propylamine. The reaction mixture was then refluxed
12- ~ ~ 0 ~
overnight for approximately 16 hours and finally cooled
to room temperature before being poured over ice/water
with mechanical stirring. The resulting aqueous mixture
was then stirred at room temperature for 30 minutes and
filtered, and the solid product so obtained was sub-
sequently washed with cold water and triturated with ethyl
acetate to ultimately afford 7.0 g.(71%) of pure 4-chloro-
7-fluoro-[1,2,4]triazolo[4,3-a]quinoxaline, m.p. 305-
308C. Mass Spectrum: m/e, 222 (P~; m/e, 224 (P+2).
Preparation B
4-chloro-l~ethyl-7-fluoro=[1,2,4]triazolo[4,3-a]quinoxaline
a) Preparation of l-ethyl-7-fluoro-4-methoxy-[1,2,4]-
triazolo-[4,3-a]quinoxaline
A mixture consisting of 15 ~. (0.07 mole) of 6-fluoro-
2-hydrazino-3-methoxyquinoxaline, the product of Preparation
A(b), and 250 ml. of triethyl or~hopropionate was heated
wi~h mechanical stirring in a preheated oil bath at 100C.
overnight (fJ 16 hours). The resulting mixture was
cooled to room temperature (~J 20C,) filtered and the
recovered precipitate washed with ethanol to afford
1].3 g. (64%) of pure 1-ethyl-7-fluoro-4-methoxy-~1,2,4]~
triazolo[4,3-a]quinoxaline, m~p. 200-202C. (decomp.).
b) Preparation of l-ethyl-7-fluoro-4-hydroxy-
[1,2,4]triazolo-[4,3~a]quinoxaline
A mixture consisting of 11.3 g (0.046 mole) of l-ethyl-
7 fluoro-4-methoxy-[1,2,4]triazolo~4 9 3-a]quinoxaline,
115 ml. of lN hydrochloric acid and 345 ml. of glacial
acetic acid was re~luxed for a period of three hours.
Upon cornple~ion of this step, the reaction mixture was
cooled to room temperature and poured over ice/water.
The resulting mixture was then stirred for a period of
30 minutes, filtered and the recovered solid product
subsequently washed with water and air-dried to ultimately
afford 6.6 g. (62%) of pure 1-ethyl-7-fluoro-4-hydroxy-
[1,2,4]triazolo[4,3-a]quinoxaline, m.p. ~ 300C, Mass
Spectrum: m/e, 232 (P); m/e, 231 ~P-l).
-13- ~ ~Q ~
c) Preparation of 4~chloro-1-ethyl-7-fluoro-[1,2,4~-
triazolo[4,3-a]quinoxaline
In a flame-dried reaction flask under a dry nitrogen
atmosphere, there were placed 6.6 g. (0.028 mole) of
l-ethyl-7-fluoro-4-hydroxy-[1,2,4]triazolo[4,3-alquinox-
aline and 120 ml. of phosphorus oxychloride together
with 6.6 ml. of tri-n propylamine. The reaction mixture
was then refluxed overnight for approximately 16 hours
and finally cooled to room termperature beore being
poured over ice/water with mechanical stirring. The
resulting aqueous mixture was then stirred at room temp-
era~ure for 30 minutes and filtered, and the solid product
so obtained was subsequently washed with cold water and
then dissolved in ethyl acetate. The latter organic
solution was then successively washed with water, satur-
ated aqueous sodium bicarbonate solution and saturated
brine before being dried over anhydrous magnesium sulfate.
After removal of the drying agent by means of filtration
and the solvent by means of evaporation under reduced
pressure 9 there was ultimately obtained a tan solid
product which was subsequently triturated with diethyl
ether to yield 4 g. (57%) of pure 4 chloro-1-ethyl-7-
fluoro-[1,2,4]triazolo[4,3-a]quinoxaline, m.p. 203-205C.
Mass Spectrum: m/e, 250 (P); m/e, 252 (P+2); m/e, 249
(P-l).
Preparation C
4,7~Dichloro-[1,2,4]triazolo[4,3-a]quinoxaline
a) Preparation of 2,3-dihydroxy-6-chloroquinoxaline
A mixture consisting of 100 g. (0,07 mole) of
4-chloro-1,2-phenylenediamine and 750 ml. of diethyl
oxalate was refluxed overnight and for a period of approx-
imately 16 hours. Upon completion of this step, the
reaction mixture was cooled to room temperature (~20C.),
filtered and the recovered product subsequently washed
with ethanol and air-dried to eonstant weight to ultimate-
ly afford 140 g. of pure 2 9 3-dihydroxy-6-chloroquinoxaline,
m.p.~ 260C.
b) Preparation of 2,3,6-trichloroquinoxaline
A mixture consisting of 1~0 ~. (0,70 mole) of 2,3-
dihydroxy-6-chloroquinoxaline and 326 ml. (3.50 mole)
of phosphorus oxychloride was re~luxed overnight
(~16 hours) and then poured over ice. The resulting
aqueous mixture was then filtered, and the recovered
product s~bsequently washed with water and air-dried
prior to being dissolved in chloroform. The latter
organic solution was then washed with saturated brine and
air-dried over anhydrous magnesium sulfate. After re-
moval of the drying agent by means of filtration and the
solvent by means of evaporation under reduced pressure,
there was ultimately obtained a thick slurry which was
recrystallized from chloroform/ethanol to afford 120g.
(74%~ of pure 2,3,6-trichloroquinoxaline, m.p. 139-1~2C.
Mass Spectrum: m/e, 232 (P); m/e, 234 (P+2); m/e,
236 (P~4).
c) Preparation of 2,6-dichloro-3-methoxyquinoxaline
A slurry consisting of 11.7 g. (0.05 mole) of
2,3,6-trichloroquinoxaline in 1~0 ml. of methanol was
heated to 50C., at which point there was added thereto
in a dropwise manner a solution consisting of 1.4 g.
~0.06 mole) of sodium dissolved in 140 ml. of methanol
over a period of six hours. The resulting mixture was
then heated at 50C. overnight (rJ16 hours), followed
by a further addition of 140 mg. of sodium in 20 ml.
of methanol over a period of one hour. The final reac-
tion mixture was then heated at 50C. for a period of
two hours and cooled to room temperature. Upon comple-
tion of this step, the spent mixture was concentratedin vacuo and dissolved in chloroform/watPr. The organic
phase was separated and saved, and the aqueous phase
further extracted with chloroform. The various organic
(i.e., chloroform) extracts were combined and successively
washed with fresh portions of water and saturated brine,
-15-
followed by drying over anhydrous magnesium sulfate. After
removal of the drying agent by means of filtration and
the solvent by means of evaporation under reduced pressure,
the residue was chromatographed on a column of 250 ml.
of silica gel and eluted with toluene. Like ~ractions
were combined to ultimately afford a white solid consist-
ing of 9.8 g. (86%) of pure 2,6-dichloro-3-methoxyquinox-
aline, m.p. 92-95C.
d) Preparation of 6-chloro-2-hydrazino-3-methoxyquinox-
aline
A mixture of 4.9 g. (0.02 mole) of 2,6-dichloro-3-
methoxyquinoxaline and 2.7 g. (0.053 mole) of hydrazine
hydrate (2.6 ml.) in 75 ml. of e~hanol was stirred at
room temperature overnight (i.e., at ca. 20C. for approx-
imately 16 hours). Upon completion of this step, theresulting mixture was filtered and the recovered precipi-
tate was washed with ethanol to ultimately afford 4.4 g.
(98%) of pure 6-chloro-2-hydrazino-3-methoxyquinoxaline,
m.p. 175-179C. (decomp.). Mass Spectrum~ m/e, 224 (P);
m/e, 226 (P-~2).
e) Preparation of 7-chloro 4-methoxy-[1,2,4]triazolo-
[4,3-a]quinoxaline
A mixture consisting o~ 1.4 g. (0.0062 mole) of
6-chloro-2-hydrazino-3-methoxyquinoxaline and 20 ml. of
triethyl orthoformate was heated with mechanical stirring
in a preheated oil bath at 100C. overnight (~J15 hours).
The resulting mixture was then cooled to room temperature,
and the precipitate which formed was subsequen~ly recovered
by means o~ suction filtration and washed with ethanol
to ultimately afford 1.0 g. (69%) of pure 7-chloro-4-
methoxy-[1,2,4]triazolo[4,3-a]quinoxaline, m.p. 250-
252C
f) Preparation of 7-chloro-4-hydroxy-[1,2,4]triazolo-
[4,3-a]quinoxaline
A mixture consisting of 3,4 g. (0.014 mole) of
~~ -16~
7-chloro-4-methoxy-[1,2,4]triazolo[4,3-a]quinoxaline,
35 ml. of lN hydrochloric acid and 105 ml. of glacial
acetic acid was refluxed ~or a period of 2.5 hours.
Upon completion of this step, the reaction mixture was
cooled to room tempera~ure and poured over ice/water.
The resulting mixture was then stirred for a period o~
20 minutes, filtered and the recovered solid product
washed with water and air-dried to constant weight to
ultimately afford 2.6 g. (87~) of pure 7-chloro-4-hydroxy-
[1,2,4]triazolo[4,3-a]quinoxaline, m.p. >300C.
g) Preparation of 4,7-dichloro-[1,2,4]triazolo~4,3-a~-
quinoxaline
In a flame-dried reaction flask under a dry nitrogen
atmosphere, there were placed 2.6 g. (0.012 mole~ of
7-chloro-4-hydroxy-[1,2,4]-triazolo[4,3-a]quinoxaline
and 40 ml. of phosphorus oxychloride together with 2,6
ml. of tri~n-propylamine. The reaction mixture was then
refluxed overnight for approximately 16 hours and finally
cooled to room temperature prior to being slowly poured
over ice/water. The resul~ing aqueous mixture was next
extracted with ethyl acetate and the latter extract
was successively washed with water, saturated aqueous
sodium bicarbonate solution and saturated brine before
being dried over anydrous magnesium sulfate. After
removal of the drying agent by means of filtration and
the solvent by means of evaporation under reduced pressure,
there was ultimately obtained a yellowish solid product
as residue which was subsequently chromatographed on
a 200 ml. silica gel column and then eluted with chloro-
form/methanol (9:1 by volume). Like fractions were then
combined and concentrated in vacuo to finally afford an
orange solid product which consisted of 1.89 g. (66~) of
pure 4,7-dichloro-[1,2,4]triazolo[4,3-a]quinoxaline, m.p.
253-256C. (decomp.). Mass Spectrum: m/e, 238 (P);
m/e, 240 (P~2); m/e, 242 (P-~4).
~ -17~ 7~2
Preparation D
4,7-Dichloro-l~ethyl-[1,2,4]triazolo[4,3-a]quinoxaline
a) Preparation of 7-chloro-1-ethyl-4-methoxy-[1,2,4]-
triazolo-[4,3-a]quinoxaline
A mixture consisting of 5.1 g. (0.022 mole) of
6-chloro-2-hydrazino-3-methoxyquinoxaline, the product of
Preparation C(d~, and 60 ml. of triethyl orthopropionate
was heated with mechanical stirring in a preheated oil
bath at 100C, overnight (ril6 hours). The resulting
mixture was then cooled to room temperature (~20C.),
and the precipitat~ which formed was subsequently collected
by means of suction filtration and washed with diethyl
ether to ultimately afford 4.3 g. (75%) of pure 7-chloro-
l~ethyl-4-methoxy-[1,2,4]triazolo[4,3-a]quinoxaline,
m.p~ 221-223~C.
b~ Preparation of 7-chloro-1-ethyl-4-hydroxy-[1,2,4]-
triazolo[4,3-a]quinoxaline
A mixture consisting of 4.3 g. (0.0072 mole) of
7-chloro-1-ethyl-4-hydroxy-[1,2,4]triazolo[4,3-a]quinox-
aline~ 40 ml. of lN hydrochloric acid and 60 ml. of
methanol was refluxed overnight and then cooled to room
temperature, The precipitate which formed was sub-
sequently collected by means of suction filtration and
washed with methanol. In this manner~ there were ulti-
mately obtained 3.7 g. (94~) of pure 7-chloro-1-ethyl-
4-hydroxy-[1,2,4]triazolo[4,3-a]quinoxaline, m.p.~ 300C.
c) Preparation of 4,7-dichloro-1-ethyl-[1,2,4]triazolo-
[4,3-a]quinoxaline
In a flame-dried reaction flask under a dry nitrogen
atmosphere, there were placed 5.1 g. (0.02 mole) of
7-chloro-1-ethyl-4-hydroxy-[1,2,4]triazolo[4,3-a]quinox-
aline and 75 ml. of phosphorus oxychloride together with
S ml~ of tri-n propylamine. The reaction mlxture was
then refluxed overnight for approximately 16 hours and
finally cooled to room temperature prior to being slowly
poured over ice/water. The resulting aqueous mixture
18~
was next stirred at room temperature for 15 minutes
and filtered, and the solid product so obtained was
subsequently washed with cold water and air-dried to
constant weight to ultimately afford 4.2 g. (79~) of
pure 4,7-dichloro-1-ethyl-[1,2,4]triazolo[4,3-a]quinox-
aline, m.p. 217-220C. (decomp.). Mass Spectrum:
m/e, 266 (P); m/e, 2~8 (P-~2); m/e, 265 (P-l).
Preparation E
4-Chloro-7-methoxy-~1,2,4]triazolo[4,3-a]quinoxaline
a) Preparation of 2,3-dihydroxy-6-methoxyquinoxaline
A mixture consisting of 20 g. (0.114 mole) of
4-methoxy-o-phenylenediamine and 11 g. (0.114 mole) of
triethylamine dissolved in 200 ml. of diethyl oxalate
was refluxed overnigh~ for a period of approximately
lS 16 hours. Upon completion of this step, the reaction
mixture was cooled to room temperature ( 20C.) and
filtered to remove the desired product. ~fter washing
with ethanol, there were ultimately obtained 14.8 g.
(68%) of pure 2,3-dihydroxy-6-methoxyquinoxaline, m.p.
> 300C. Mass Spec~rum: m/e, 192 (P).
b) Preparation of 2,3-dichloro-6-methoxyquinoxaline
In a flame dried reaction flask under a dry nitro-
gen atmosphere, there were placed 14.8 g~ (0.077 mole)
of 2,3-dihydroxy-6-methoxyquinoxaline and 75 ml. o~
phosphorus o~ychloride toge~her with 15 ml. of tri-n-
propylamine. The exothermic reaction mixture was then
allowed to stir at room temperature ( 20C.) ~or a
period of one hour and -thereafter was refluxed overnight
(~ 16 hours). Upon completion of this step, the reaction
mixture was again cooled to room temperatur~ and finally
poured slowly over ice/water. The resulting aqueous
mixture was then stirred at room temperature ~or a period
of 20 minutes, filtered and the recovered precipitate
washed with water prior to being dissolved in chloroform.
The latter solution was then filtered to remove insoluble
-19~
i
material and the filtra~e so obtained was successi~ely
washed with water, satura-ted sodium bicar~onate solution
and saturated brine. Concentration of ~he washed solution
in vacuo, followed by recrystallization of the residue
from ethanol, then gave 14.2 g. (80~) of pure 2,3-dichloro-
5-methoxyquinoxaline, m.p. 156-159C. Mass Spectrum:
m/e, 228 (P); m/e, 230 (P+2); m/e, 232 (P~4).
c) Preparation of 2-chloro-3,6-dimethoxyquinoxaline
In a flame-dried reaction flask under a dry nitrogen
atmosphere, there was slowly added a solution consisting
of 850 mg. of sodium dissolved in 80 ml. of methanGl to a
slurry of 7.1 g. o~ 2,3-dichloro-6-methoxyquinoxaline
in 60 ml. of methanol at 50C. over a period of seven
hours. The resulting mixture was then heated at 50C.
overnight and finally cooled to room temperature. Upon
completion of ~his step, the spent reaction mixture
was concentrated in vacuo and the residue subsequently
dissolved in chloroform, followed by washing with water
and drying over anhydrous magnesium sulfate. After
removal of the drying agent by means of filtration and
the solvent by means of evaporation under reduced pressure,
th2 resulting residue was subsequently chromatographed
on a column of 400 ml. of silica gel, followed by elu-
tion with toluene. The good fractions were combined
and concentrated in vacuo to ultimately afford a white
solid consisting of 6.1 g (88%) of pure 2-chloro-3,6-
methoxyquinoxaline. m.p. 79-81~C.
Anal. Calcd. for CloHgClN202 C, 53.47; H, 4.04;
N, 12.47. Found: C, 53.29, EI, 4.05; N, 12.28.
d) Preparation of 3,6-dimethoxy-2-hydrazinoquinoxaline
A mixture consisting of 5 ~. (0.022 mole) of 2-c~loro-
3,6-dimethoxyquinoxaline and 2.8 g. (0.056 mole) of
hydrazine hydrate (2.7 ml.) in 75 ml. of ethanol was
heated a~ 50C. overnight. Upon completion of this step,
~ -20~ 7~
a further 1.0 ml. of hydrazine hydrate was added to the
mixture and the resulting mixture was heated at 50C.
for a period of six hours. ~t this point, another 1.0
ml. of hydrazine hydrate was added and the final reaction
mixture was heated at 50C. overnight prior to being
cooled to room temperature. The spent mixture was then
filtered and the recovered precipitate washed with ethanol
to ultimately afford 4.1 g. (~5%) of pure 3,6-dimethoxy-
2-hydrazinoquinoxaline, m.p. 128-130C. (decomp~).
e) Preparation of 4,7-dimethoxy-[1,2,4]triazolo[4,3-a]-
quinoxaline
A mixture consisting of 1.5g. (0.068 mole) of
3,6-dimethoxy~2-hydrazinoquinoxaline and 20 ml. of tri-
ethylorthoformate was heated with mechanical stirring in
a preheated oil bath at 100C. overnight ( 16 hours).
The resulting mixture was then cooled to room tempera-
ture, and the precipitate which formed was subsquently
recovered by means of suction fiitration and washed with
ethanol to ultimately afford 1.8 g. of pure 4,7-dime~hoxy-
[1,2,4]triazolo[4,3-a]quinoxaline, m.p. 238-240C. (de-
comp.). Mass Spectrum: m/e, 230 (P); m/e, 231 (P+l);
m/e, ~32 (P+2).
f) Preparation of 4-hydroxy-7-methoxy-[1,2,4]triazolo
[4,3-a]quinoxaline
A mixture consisting of 1.6 g. (0.0069 mole) of
4,7-dimethoxy-[1,2,4]triazolo[4,3-a]quinoxaline, 16 ml.
of lN hydrochloric acid and 48 ml. of glacial acetic acid
was refluxed for a period of three hours. Upon completion
of this step, the reaction mixture was poured over ice
and filtered. The recovered product was then collected
on the filter funnel and washed with diethyl ether to
ultimately afford 1.19 g. (80%) of pure 4-hydroxy-7-methoxy-
[1,2,4]triazolo[4,3-a]quinoxaline, m.p. ~250C.
g) Prepara~ion of 4-chloro-7-methoxy-[1,2,4]triazolo-
[4,3-a~quinoxaline
In a flame-dried reaction flask under a dry nitrogen
atmosphere, there were placed 1.1 g. (0.0055 mole) of
- 2 1 - ~L2~734~7Z
4-hydroxy-7-methoxy-[1,2,4]triazolo[4,3-a]quinoxaline
and 15 ml~ oE phosphorus oxychloride together with
1.0 ml. o~ tri-n-propylamine. The reaction mixture was
then refluxed overnight ~or approximately 16 hours and
finally cooled to room temperature prior to being slowly
poured over ice/water. The resulting aqueous mixture
was next extracted wi-th ethyl acetate, and the latter
extract was successively washed with water and saturated
brine before being dried over anhydrous magnesium sulfate.
After removal oE the drying agent by means of filtration
and the solvent by means of evaporation under reduced
pressure, there was ultimately obtained a residual product
that was subsequently chromatographed on a 150 mlO silioa
gel column and then eluted with chloro~orm/methanol
lS (95:5 by volume). Like fractions containing the product
were then combined and concentrated in vacuo to finally
afford a residual material, which was recrystallized
from chloroform/diethyl ether to yield 400 mg. (31%)
of pure 4~chloro-7-methoxy-[1,2,4]triazolo[4,3-a]quinox-
aline, m.p. 266-268C. (decomp.). Mass Spectrum: m/e,
234 (P); m/e, 236 (P+2).
Preparation F
4-Chloro-l-ethyl-7-methoxy-[1,2,4]triazolo[4,3-a]quinoxaline
a) Preparation of l-ethyl-4,7 dimethoxy-[1,2,4]triazolo-
[4 9 3-a~quinoxaline
A mixture consisting of 4.0 g. (0.018 mole) of
3,6-dimethoxy-2-hydrazinoquinoxaline, the product of
Preparation E(d), and 50 ml. of triethyl orthopropionate
was heated with mechanical stirring in a preheated oil
bath at 100C. overnight (~J16 hours). The resulting
reaction mixture was then cooled to room temperature
(~J20C.), and the precipitate which formed was subse
quently recovered by means of suction filtration and
washed with ethanol to ultimately afford 3.3 g. ~72%) of
pure 4,7-dimethoxy-1-ethyl-[1,2,4]txiazolo[4,3-a]quinox-
aline, m.p. 184-188C. Mass Spectrum: m/e, 258 (P);
m/e, 228 (P-30).
~r --2 2 ~
b) Preparation of l-ethyl-~-hydroxy-7-methoxy-[1,2,4]-
triazolo[4,3-a]quinoxaline
A mixture consisting of 3,3 g (0.013 mole) o
4,7 dimethoxy-1-ethyl-[1,2,4]triazolo[4,3-a]quinoxaline,
33 ml. of lN hydrochloric acid and 99 ml. of glacial
acetic acid was refluxed for a period of two hours. Upon
completion of this step, the reaction mixture was cooled
to room tempera~ure and poured over ice/water. The
resulting mixture was then stirred for a period of 20
minutes and extracted with ethyl acetate. The latter
extract next washed with saturated brine and dried over
anhydrous ma~nisium sulfate. After removal of the drying
agent by means of filtration and the solvent by means of
evaporation under reduced pressure, there was finally
obtained a yellowish solid produc~ which was washed with
water and air-dried to constant weight to ul~imately
afford 1.~7 g. (67%) of pure 1-ethyl-4-hydroxy-7-methoxy-
[1,2,4~triazolo[4,3-a]quinoxaline, m.p. ~250C.
c) Preparation of 4-chloro-1-ethyl-7-methoxy~[1,2,4]-
triazolo[4,3-a]-quinoxaline
In a flame dried reaction flask under a dry nitrogen
atmosphere, there were placed 1.87 gO (0.0076 mole) of
l-ethyl-4-hydroxy-7-methoxy-[1,2,4]triazolo[4,3-a]quinox-
aline and 25 ml. of phosphorus oxychloride together with
1.8 ml. of tri-n-propylamine. The reaction mixture
was then refluxed overnight for approximately 16 hours
and finally cooled to room temperature prior to being
510wly poured over ice/water. The resulting aqueous
mixture was then stirred at room temperature for 30
minutes and ~iltered, and the solid product so obtained
was subsequently washed with cold water and then dis-
solved in chloroform. The latter organic solution was
thereafter washed with saturated brine and dried over
anhydrous magnesium sulfate. After removal of the drying
agent by means of filtration and the solvent by means
of evaporation under reduced pressure, there was finally
-23~
obtained a yellow solid product which was triturated
with diethyl ether and filtered to ultimately a~ford
1.6 g. (80%) of pure 4-chloro-1-ethyl-7-methoxy-[1,2,4]-
triazolo[4,3 a]quinoxaline, m.p. 173~175C. Mass
Spectrum: m/e, 262 (P); m/e, 264 (P+2); m/e, 261 (P 1).
Preparation G
4-Chloro-8-fluoro-[1 2 4]triazolo[~3-a]quinoxaline
a) Preparation of 2,3-dihydroxy-6-1uoroquinoxaline
A mixture consisting of 26.3 g. (0.19 mole) of
4-fluoro-1,2-phenylenediamine [Journal of the_American
Chemical Society, Vol. 75, P.1294 ~1953)] and 150 ml.
of diethyl oxalate was refluxed under a nitrogen at-
mosphere ~or a period of 18 hours. Upon completion of
this step, the reaction mixture was cooled to room temp-
erature (~20C.), filtered and the recovered product
subsequently washed with four-100 ml. portions of ethanol
and air-dried ~o constant weigh~ to ultimately afford
19~3 g. (80~) of pure 2,3-dihydroxy-6-fluoroquinoxaline,
m.p. ~300Co (literature m.p. 387-390C., according to
U.S. Patent No. 3,992,378). Mass Spectrum: m/e, 180 (P+).
b) Preparation of 2,3-dichloro-6-fluoroquinoxaline
A mixture consisting of 19 g. (0.105 mole of 2,3-
dihydroxy-6-fluoroquinoxaline and 50 ml. of phosphorus
oxychloride was refluxed overnight (~16 hours) and
then cooled to room temperature prior to being poured
over 200 g. of ice with good stirring. The resulting
aqueous mixture was then filtered, and the recovered
product subsequently washed several tîmes with water
to ultimately afford 28.2 g. of 2,3-dichloro-S-fluoro-
quinoxaline, m.p. 148-152G.
c) Preparation of 2-chloro-6-fluoro-3-hydrazinoquin-
oxaline
To a suspension of 28.2 g. (0.105 mole) of
2,3-dichloro-6 fluoroquinoxaline in 500 ml. of ethanol,
there were added 15 ml. (0.31 mole) of hydrazine hydrate
, -24- ~ z ~
over a period o~ two minutes to give a dark red suspen-
sion. The resul~ing mixture was then stirred under a
nitrogen atmosphere at room temperature for a period
of 20 hours. At this point, the precipitate was flltered
and washed several times with ethanol, followed by air-
drying to constant weight to ul~imately afford 20.7 g.
(93%) of pure 2-chloro-6-fluoro-3~hydrazinoquinoxaline,
m.p. 190~192C. (decomp.).
d~ Preparation of 4-chloro-8-fluoro-[1,2,4]triazolo-
[4,3-a]quinoxaline
A mixture consisting of 10 g. (0.047 mole3 of
2-chloro-6-fluoro-3-hydrazinoquînoxaline and 80 ml.
(0~47 mole) of triethyl orthoforrnate was heated under a
nitrogen a~mosphere with mechanical stirring in a pre-
heated oil bath at 100C. overnight (~ 16 hours). The
resulting mixture was cooled to room temperature, and the
precipitate which formed was subsequently recovered by means
of suction filtration, washed with three~50 ml. portions
of ethanol and air dried to constant weight to ultimately
afford 9.42 g. (91%) of pure 4-chloro-8-fluoro-[1,2,4]-
triazolo~4,3-a]quinoxaline, m.p. 310-312C. (decomp.).
Mass Spectrum: m/e, 224, 223, 222 (P+~.
Preparation H
4-Chloro-l-ethyl-B-fluoro-[1,2,4]triazolo[4,3-a]quinoxaline
A mixture consisting of 10.0 g. (0.047 mole) of
2-chloro-6-fluoro-3-hydrazinoquinoxaline9 the product of
Preparation G(c), and 95 ml. (0.47 mole) of triethyl orth
propionate was heated under a nitrogen atmosphere with
mechanical stirring in a preheated oil bath at 100C.
overnight (~J16 hours). The resulting mixture was cooled
to room temperature (~ 20C.), and the precipitate which
formed was subsequently recovered by means of suction
filtration, washed with three 50 ml. portions of ethanol
and air-dried to constant weight to ultimately afford 7.5 g.
(65%) of pure 4-chloro-1-ethyl-8-fluoro-[1,2,4]triazolo-
[4,3-a]quinoxaline, m.p. 160-163C. (decomp.). Mass
Spec~rum: m/e, 249, 250, 251, 252 (P+).
~ ~5-
:~LZ~
Preparation I
4-Chloro~8-fluoro-1-trifluoromethyl-[1,2,4]triazolo[4,3-a]-
~uinoxaline
a) Preparation of 8-fluoro-4-hydroxy-1-trifluoromethyl-
[1,2,4]triazolo[4,3-a]quinoxaline
A mixture consisting of 12.8 g. (0.06 mole) of
2-chloro-6-fluoro-3-hydrazinoquinoxaline in 50 ml. (0.65
mole) of trifluoracetic acid was heated under a dry
nitrogen atmosphere at 120C. for a period of 24 hours
with the aid of mechanical stirring to give a homogeneous
solution The resulting reaction mixture was then poured
with stirring over ice/water, stirred for an additional
30 minutes and filtered. The product so obtained was
thereafter washed with three~-separate portions o~ water
and dried in vacuo at 80C. to ultimately afford 12.58 g.
(77%) of pure 8-fluoro-4-hydroxy-1-trifluoromethyl-
[1,2,4]triazolo[4,3-a]quinoxaline, m.p. 298-302C.
Mass Spectrum: m/e, 272 (P+).
b) Preparation of 4-chloro-8-fluoro-1-trifluoromethyl-
[1,2,4]triazolo[4,3-a]quinoxaline
In a flame-dried 250 ml. three-necked reaction
flask under a dry nitrogen atmosphere, there were placed
12.5 g. (0.046 mole) of 8-fluoro-4-hydroxy-1-trifluoromethyl-
[1,2,4]triazolo[4,3-a]quinoxaline and 85 ml. of phosphorus
oxychloride together with 17.5 ml. of tri n-propylamine.
The reaction mixture was then refluxed overnight for
approximately 16 hours and finally cooled to room tem-
perature (~J20C.) prior to being slowly poured over 1000
ml. of ice/water with the aid of mechanical stirring,
The resulting aqueous mixture was next stirred for an
additional period of 30 minutes at room temperature,
followed by extraction with three-300 ml. portions of
chloroform. The combined chloroform layers were then
successively washed with saturated aqueous sodium
bicarbonate solution, water and saturated brine and
finally dried over anhydrous magnesium sulfate.
`` -26- ~ 72
After removal of the drying agent by means of iltration
and the solvent by means o evaporation under reduced
pressure, there was Einally obtained a yellow solid product
which consisted of 10.47 gO (79~) of pure 4-chloro-8~
fluoro-1-trifluoromethyl-[1,2,4]triazolo[4~3-a]quinoxaline,
m.p. 135-138C. Mass Spectrum: m/e, 292/290 (P+).
Preparation J
4-Chloro-7,8~difluoro-[1,2,4]triazolo[4,3-a]quinoxaline
a) Preparation of 2,3-dihydroxy-6,7-difluoroquinoxaline
A mixture consisting of 11.3 g~ (0.0784 mole) of
4,5-difluoro-o~phenylenediamine (U.S. Patent No. 4,264,600
and 80 ml. (0~589 mole3 of diethyl oxalate was re1uxed
for a period of four hours to give a thick precipitate
of product. The spent reaction mixture was then cooled
to room temperature ( 20C.) overnight, filtered and
the solid product so obtained was thereafter washed
several times with diethyl ether and air-dried to
constant weight to ultimately afford 15.5 g of pure
2,3-dihydroxy-6,7-difluoroquinoxaline, m.p. ~310C..
Mass Spectrum: m/e, 198 (P~).
b~ Prepara~ion of 2,3-dichloro-6 9 7-difluoroquinoxaline
A mixture consisting of 15.4 g. (0.078 mole) of
2,3-dihydroxy-6,7-difluoroquinoxaline, 39 g. (0.187 mole)
o~ phosphorus pentachloride and 20 ml. (0.22 mole) of
phosphorus oxychloride was refluxed with stirring for
a period of four hours, during which time an additional
amount of 20 ml. of phosphorus oxychloride was added to
facilitate the stirring (the reaction mixture become
homogeneous within 30 minutes). Upon completion of this
step, the reaction mixture was stirred overnight ( 16
hours) at room tempera~ure to give a light yellow preci-
pitate. The spent mixture was then poured over 200 gO of
ice/water and ~urther stirred with additlonal cooling
to give a tan solid which consisted of 20.9g of 2,3-
dichloro-6,7-difluororquinoxaline, m.p. 162-164C.
(decomp.). Mass Spectrum: m/e, 238/236/234 (P+).
~ -27- ~2~7~7~
c) Preparation of 2-chloro-6,7-difluoro-3-hydrazino~
quinoxaline
A mixture consisting of 10 g. (0.0426 mole) of
2,3-dichloro-6,7~difluoroquinoxaline and 5 ml. (0.03 mole)
of hydrazine hydrate in 200 ml. of ethanol was stirred
at room temperature for a period of 24 hours to give
a rust-red precipitate. The thick slurry was filt~red
and the recovered produc~ washed with two-20 ml. portions
of ethanol, followed by air-drying to cons~ant weight to
ultimately afford 5.99 g (67%) of pure 2-chloro-6,7-
difluoro-3-hydrazinoquinoxaline, m.p. 212-215C. (deco~p.).
Mass ~pectrum: m/e, 230 (P); m/e, 232 ~P+)7
d) Preparation of 4-chloro-7 9 8-difluoro-[1,2,4]triazolo
[4,3-a]quinoxaline
A mixture consisting of 5.99 g. (0.026 mole) of
2-chloro-6,7-difluoro-3-hydrazinoquinoxaline and 30 ml.
(0.18 mole) of trie~hyl orthoformate was heated at 100C.
for a period of 24 hours to give a red~brown solid. The
resulting slurry was then cooled to room temperature
and filtered, and the recovered product subsequently
washed with diethyl ether ~o ultimately affoxd 5.15 g.
(82%) of pure 4-chloro-7,8-difluoro-[1,2,4]triazolo[4,3-a]-
quinoxaline, m.p.~ 210C. (decomp.). Mass Spectrum:
m/e, 242/240 (P~).
Preparation K
4-Chloro-6,7-difluoro-I-ethyl-[1,2,4]triazolo[4,3-a]-
quinoxaline
A mixture consisting of 7.0 g. (0.03 mole) of
2-chloro-6~7 difluoro-3-hydrazinoquinoxaline, the product
of Preparation J(c), and 60 ml. (0.30 mole~ of triethyl
orthopropionate was heated under a nitrogen atmosphere with
mechanical stirring in a preheated oil bath at 100C.
for a period of 24 hours. The resulting mix~ure was
cooled to room temperature (~ 20C.), and the red pre-
cipitate which formed was subsequently recovered by
means of suction filtration, washed with two separate
- -~8-
` ~Z~7~Z
portions of diethyl ether and air-dried to constant
weight to ultimately afford 4.15 g (52~) of pure
4-chloro-6,7-difluoro-1-ethyl-[1,2,4]triazolo[4,3-a]-
quinoxaline, m.p. 185-186C. (decomp.).
5Preparation L
4,8-~ichloro-1-methyl-~1,2,4]triazolo[4,3-a]quinoxaline
a) Preparation of 2,6-dichloro-6-hydrazinoquinoxaline
A mixture consisting of 23 g. (0.10 mole) of 2,396-
trichloroquinoxaline and 11 g, (0.22 mole) of hydrazine
hydrate in 500 ml. o ethanol was stirred at room
temperature (^J20C.) overnight (~ 16 hours). The
precipitate which formed was separated by filtration
and washed with ethanol to ultimately afford 22,2 g. (97%)
of pure 2,6-dichloro-3-hydrazinoquinoxaline, m.p. > 250C~
Mass Spectrum: m/e, 228 (P).
b) Preparation of 4,8-dichloro-1-methyl-[1,2,4]triazolo-
[4,3-a]quinoxaline
A mixture consis~ing of 20 g. (0.087 mole) of
2,6-dichloro-3-hydrazinoquinoxaline and 160 ml. (0.87
mole) of triethyl orthoacetate was heated with mechanical
stirring under a dry nitrogen atmosphere in a preheated
oil bath at 100C. for a period of 20 hours to give a
yellow suspension. The resulting mixture was cooled to
room temperature and ~ ered, and the recovered solid
product was subsequently washed with ethanol and air-
dried to constant weight to ultimately afford 10.2 g~
(46%) of pure 4,8-dichloro-1-methyl-[1,2,4~triazolo[4,3-a3-
quinoxaline, m.p. ~ 280C. Mass Spectrum: m/e, 254/252 (P+).
Preparation M
4~8-Dichloro-l-trifluoromethyl-[1,2,4]triazolo[4,3-a3-
qùinoxaline
a~ Preparation of 8-chloro-4-hydroxy-1 tri~luoromethyl-
[1,2,4]triazolo[4,3-a]quinoxaline
In a flame-dried 500 ml. three-necked reaction
flask equipped with mechanical stirrer, nitrogen-inlet
~~ -29 ~ 7~
tube and reflux condenser, there were placed 67 ml.
(0.87 mole) of -trifluoroacetic acid. S~irring was commenced
and 20 g. (0.087 mole)of 2,6-dichloro-3-hydrazinoquinox-
aline, the product of Preparation L(a) were added thereto.
The resulting reaction mixture was then heated on a steam
bath for a period of 2~ hours, cooled to room temperature
(~ 20C.) and poured over 200 g. of ice/water. The aqueous
mixture so obtained was then stirred for 30 minutes,
filtered and the recovered product subsequently washed
several times with water and air-dried to constant weight
(required approximately 18 hours). In this way, there
were ul~imately obtained 14.3 g. (57%) of pure 8-chloro-
~-hydroxy-l-trifluoromethyl [1,2,4]triazolo[4,3-a]quinoxa-
line, m.p. 253-255C. (decomp.) Mass Spectrum: m/e,
290/288 (P+).
b) Preparation of 4,8-dichloro-1-trifluoromethyl-[1,2,4]-
triazolo[4,3-a]quinoxaline
In a flame-dried 250 ml. three-necked reaction flask
equipped wi~h mechanical stirrer, dropping funnel and
reflux condenser, under a nitrogen sweep, there were
placed 14.3 g. (0.05 mole) of 8-chloro-4-hydroxy-1-tri-
fluoromethyl-[1,2,4]triazolo[4,3-a]quinoxaline in 100 ml.
of phosphorus oxychloride. To the resulting suspension,
there were then added in a dropwise manner 1~ ml. (OolO
~5 mole) of tri-n-propylamine over a period of five minutes.
The resulting reaction mixture was then refluxed for a
period of 20 hours to give a clear dark wine-red solution~
Upon completion of this step, the clear solution so
obtained was cooled to room temperature and poured over
1000 ml. of ice/water with the aid of strong mechanical
stirring. The resulting aqueous mixture was then stirred
at room temperature for a period of 30 minutes and next
extracted with three-500 ml. portion of chloroform. The
latter organic extracts were subsequently combined and
then successively washed with water, saturated aqueous
7772
sodium bicarbonate solution, wa-ter and saturated brine,
followed by drying over anhydrous magnesium sulfate. A~ter
removal of the drying agent by means of Eiltration and
the solvent by means of evaporation under reduced pressure,
there was finally obtained a yellow solid which consisted
of 11.4 g. (75%) of pure 4,8-dichloro-1-tri~luoromethyl-
[1,2,4]triazolo[4,3-a]quinoxaline, m.p. 133-135C~
Mass Spectrum: m/e, 308 (Pt2); m/e, 310 (P-~4).
Preparation N
4,8-Dichloro-l-phenyl-~1,2,4]triazolo[4,3-a]quinoxaline
In a 250 ml~ three-necked reaction flask equipped
with mechanical stirrer and reflux condenser, there were
placed 50.0 g. (0,274 mole) of trimethyl orthobenzoate
that had been preheated to ca. 70C. Stirring was com-
menced and 10.0 g (0.0437 mole) of 2,6-dichloro-3-hydra-
zinoquinoxaline, the product of Preparation L(a), were
added thereto. The resulting reaction mixture was then
heated at ca. 120C., with continued stirring, for a
period of 24 hours, followed by cooling to room temper-
ature ( 20C.) and stirring overnight for approximately
16 hours to give a yellow slurry, The latter slurry
was then filtered, and the recovered solid product was
subsequently washed with two-50 ml. portions of ethanol
and air-dried to constant weight to ultimately afford
9.8 g. (72%~ of crude 4,8-dichloro-1-phenyl-[1,2,4]triazolo-
~4,3-a]quinoxaline, m.p. 305-307C. Mass Spectrum: m/e,
316/314 (P+).
z
-31-
Example 1
2-Chloro-3-hydrazinoquinoxaline
2,3-Dichloroquino~aline (33.5 g., 0.168 mole)
was stirred with hydrazine hydrate (18.5 g,, 0.369 mole)
in 500 ml. of ethanol at room temperature overnight
(i.e., at ca. 20C. for approximately 16 hours). The
thick, yellow slurry was filtered and the precipitate
was washed with ethanol. The precipitated material was
recrystallized from hot methanol -to give 13.5 g, (41%
yield) of 2-chloro-3-hydrazinoquinoxaline, m.p. 181C.
(decomp.). Mass spectrum: m/P~ 194 (P) .
Example 2
4-Chloro-[1,2,4]triazolo E4, 3-a]qui oxaline
2-Chloro-3-hydrazinoquinoxaline (9.0 g., 0~046
mole), the product of Example 1, was stirred with
trie~hyl orthoformate (90 ml.) at 100C. for one hourO
The mixture was cooled to room temperature and the
solid precipitate was collected by filtration
and washed with cyclohexane and dried to aford 8.8 gc
(94% yield) of 4-chloro-[1,2,4]triazolo[4,3-a]quinoxaline,
m.p. 287-290C. (decomp.). Mass spectrum: m/e, 204 (P).
Example 3
4-Chloro-l-meth 1-[1 2 4]triazolo[4 3-a]quinoxaline
Y 9 ~ t
2-Chloro-3-hydrazinoquinoxaline (15.5 g., 0.080
mole~, the product of Example 1, was stirred with
triethyl orthoacetate for 3 hours at 100C. The mixture
was cooled to room ~emperature and the solid
precipitate was collected by filtration9 washed
with ethanol and air dried to afford 11.4 g, (65% yield)
of 4-chloro-1-methyl-~1,2,4]triazolo[4,3-a]quinoxaline,
m.p. 215-222C. Mass spectrum: m/e; 218 (P)~
~ 3~_ ~2~ 2
Example 4
4-Chloro-l-ethyl-[1,2,4]triazolo[l~,3-a]quirloxaline
2 Chloro-3-hydrazinoquinoxaline (4.5 g., 0.023
mole), the product of Example 1, was stirred with
triethyl orthopropionate (50 ml.) at 100C, for one
hour. The mixture was cooled to room temperature
and the white precipitate was collected by filtration
and washed with cyclohexane to give 4.5 g. (85~ yield)
of 4-chloro-1-ethyl-[1,2,4]triazolo[4,3-a]quinoxaline,
m.p. 158-160C. Mass spectrum: m/e, 232 (P).
Example 5
4-Chloro-l-n-propyl~[1,2,4]triazolo[4,3-a]quinoxaline
2-Chloro--3-hydrazinoquinoxaline (3.0 g., 0.015
mole), t~e product of Example 1, was stirred with
triethyl orthobutyrate (27 ml.) at 100C. for 2 hours.
The mixture was cooled to room temperature, and the
precipitate was collected by filtration and washed
with cyclohexane. The crude solid was taken up in
chloroform and filtered to remove insoluble material.
The chloroform solution was concentrated in vacuo
to give a solid which was recrystallized from
chloroform to give 1.96 gO (53% yield) of 4-chloro-1-
n-propyl-[1,2,4~triazolo[4,3-a]quinoxaline, m.p. 173-175C.
Mass spectrum: m/e, 246 tP).
Example 6
4-Chloro-1 iso~opyl [1,2,4]triazolo[4,3a]quinoxaline
2-Chloro-3-hydrazinoquinoxaline (4.0 g., 0.02 mole),
the product of Example 1, was stirred with triethyl
orthoisobutyrate (15 ml.) at 100C. for three hours. The
solution was cooled to room temperature and the
precipitate was collected by filtration and washed
with ethanol. The crude solid was recrystallized
from 300 ml. of hot ethanol to afford 2.06 g. t40%
yield) o~ 4-chloro-1-isopropyl-~1,2,4]triazolo[4,3a]-
quinoxaline, m.p. 208-210C. Mass spectrum: m/e,
246 (P).
-33-
~ 7~
Example_7
4-Methylamino-[1,2 ? 4]triazolo[4~3-a]quinoxaline
4-Chloro-[1,274]triazolo-[4,3-a]quinoxaline (2.0 g.,
0 01 mole), the product of Example 2, in N,N-dime-thyl
formamide (30 ml.) was saturated with monomethylamine
gas and stirred at room temperature for 3 hours.
Monomethylamine gas was again bubbled into the solu-tion
and the solution was stirred at room ~empera-ture
for an additional 2 hours. The precipitate was
separated by filtration and washed with N,N-dimethyl
formamidP. Recrystallization from N,N-dimethyl-
formamide gave 1.37 g. (69% yield) of 4-methylamino-[1,2,4]-
triazolo[4,3-a]quinoxaline9 m.p.~300C. Mass spectrum:
m/e, 199 ~P).
Anal. Calcd. for CloH9N5: C, 60,29; H, 4.55; N, 35.15.
Found: C, 59.99; H, 4.47; N, 35011.
Example 8
4-Dimethylamino-[1,2J4]triazolo[4?3-a]quinoxaline
A slurry of 2.0 g. (0.01 mole) of 4-chloro-[1,2,4]-
triazolo[473-a]quinoxaline (the product of Example 2) in
N,N-dimethylformamide (30 ml.) was saturated with
dimethylamine gas and stirred at room temperature
overnight. The mixture was poured over ice and the
precipitate was removed by fil~ration. Recrystallization
from ethanol gave 640 mg. (44% yield) of 4~dimethyl-
amino-[1,2?4]triazolo[4,3-a]quinoxaline, m.p. 184-186C.
Mass spectrum: m/e, 213 ~P).
Anal. Calcd. for CllHllN5: C, 61~96; H~ 5.20; N, 32.84.
Found: C, 62.26; H, 5.43; N, 32.92.
f ~ -34-
3777~
Example 9
4-Ethylamino-[1,2,4]tri~zolo[4,3-a]quinoxaline
A slurry of 2.0 g. (0.01 mole) of 4-chloro-[1,2,4]-
triazolo[4,3-a]quinoxaline (the product of Example 2) in
s N,N-dimethylformamide (30 ml.) was saturated with mono-
ethylamine gas and stirred at room temperature for 2 hours.
Monoethylamine gas was again bubbled through
the mixture and stirring was continued for 2 hours.
The precipitate was removed by filtration and washed with
N,N-dimethylformamide. Recrystallization from methanol
afforded 680 mg. (32% yield) 4-ethylamino-[1,2,4]-
triazolo[4,3-a]quinoxaline, m.p. 254-6C. Mass spectrum:
m/e, 213 (P).
Anal- Calcd. for CllHllN5: C, 61.96; H, 5.20; N, 32q~4.
Found: C, 61.93; H, 5.09; N, 32.72.
Example 10
4-Diethylamino-[1,2,4]triazolo[4,3-a]quinoxaline
4-Chloro-[1,2,4]triazolo[4,3~a]-quinoxaline (4,4 g.,
0.021 mole), the product of Example 2, was stirred with
diethylamine (6.5 ml., 0.063 mole) in N,N-dimethylformamide
(100 ml.) at room temperature for 2 hours. The reaction
mixture was poured over an ice-water mixture to form a crude
precipitate as product, which was subsequently filtered and
washed with waterO Recrys-tallization from isopropanol gave
3.36 g. (66% yield) of 4-diethylamino-[1,2,4]triazolo[4,3-a~-
quinoxaline, m p. 117-119C. Mass spectrum: m/e, 241 (P).
3LZ~
-35
Example 11
4-Di-n~opylamino-[1,2,4]triazolo[4,3a]quinoxaline
4~Chloro-[1,2,4]triazolo[4,3-a]-quinoxaline (2.0 g.,
0.01 mole), the product of Example 2, and 3.0 g. (0.03
mole) of di~n-propylamine in N,N~dimethylformamide (50 ml.)
were stirred for 3 hours at room temperature. The solution
was poured over ice to form a precipitate which was
separated by filtration and air dried. Recrystallization
from cyclohexane (250 ml.) afforded 1.1 g, (41% yield) of
4-di-n-propylamino-[1,2,4]triazolo[4,3-a]quinoxaline,
m.p. 240-242~C. Mass spectrum: m/e, 269 (P).
Anal. Calcd. ~or C15HlgN5: C, 66.89; H, 7.11; N, 26-00-
Found: C, 66.68; H; 6.97; N, 26.12.
Exa~le 12
4-Isopropylamino~[1,224]triazolo[4,3-a]quinoxaline
4-Chloro-[1,2,4]triazolo[4,3-a]-quinoxaline (2,0 g.,
0.01 mole), the product of Example 2, and 1.77 g. (0.03
mole) of isopropylamine in N,N-dimethylformamide (30 ml.)
were stirred at room temperature overnight. The dark
solution was poured over ice and the precipitate which
was produced was separated by filtration and washed
with water. The crude product was recrystallized from
ethanol and then twice from isopropyl ether to afford
1.2 g. (53% yield) o~ 4-isopropylamino-[1,2,4]triazolo-
[4,3-a]quinoxaline, m.p. 133-5C. Mass spectrum:
m/e, 222 (P).
Anal- Calcd- for C12H13N5 1/3H2 C, 61-79;
H, 5.90; N, 30~02.
Found: C, 61.51; H, 5.89; N, 29.90.
~7~
-36-
Example I3
4-Diethylamino-l-methyl-[1,2,4]triazolo[4,3-a]quinoxaline
This compound was prepared by the method of
Example 11, utilizing 4-chloro-l-methyl-[1,294]triazolo-
[4,3-a]quinoxaline (the product of Example 3) as starting
material in place of 4~chloro-[1,2,4]triazolo[4,3-a]quin-
oxaline (the product of Example 2) and diethylamine as
reagent in place of di-n-propylamine. The crude product
obtained was recrystallized from chloroform and then from
cyclohexane to afford 7.2 g. (54% yield~ of pure 4-
diethylamino-l-methyl-[1,2,4]triazolo[4,3-a]quinoxaline,
m.p. 123-5C.
Example 14
4-Amino-l-ethyl-[1,2,4]triazolo[4,3-a]quinoxaline
Ammonia gas was bubbled through a solution of
1.2 gO (0.005 mole) of 4-chloro-1-ethyl-[1,2,4]triazolo-
[4,3a]quinoxaline (the product of Example 4) in N,N-dimethyl-
formamide (20 ml.~ at 0C. for about 2 minutes. The solution
was stirred at 0C. for 30 minutes and at room temperature
for one hour~ The reaction mixture was then poured over ice
and stirred for 20 minutes. The precipitate which formed was
removed by filtration, washed with water and air dried.
Recrys~alliza~ion from ethancl afforded 220 mg. (22%
yield) of pure 4-amino-1-ethyl-[1,2~4]triazolo[4,3-a]-
quinoxaline, m.p. 284-8C. Mass spectrum: m/e, 213 (P).
AnalO Calcd. for CllHllN5 1/6H2 C~ 61-10;
H, 5.28; N, 32.39.
Found: C, 61.36; H, 5.14; N, 31.96.
_37~ 77~
~.
Example 15
4-Methylamino-l-ethyl-~1,2~]triazolo[4,3-a]quinoxaline
Monomethylamine gas was bubbled through a
solution of 4-chloro-1-ethyl-[1,2,4]triazolo[4,3-a]-
quinoxaline (1.2 g., 0.005 mole), the product of Example
4, in N,N-dimethylformamide ~S0 ml.) at 0C. for 2 minutes~
The reaction mixture was stirred at 0C. or 30
minutes, at room temperature for 2 hours, and then poured
over ice and stirred another 20 minutes. The
pxecipitate which formed was separated by filtration,
washed with water and air dried. Recrystallization from
ethanol then aforded 1.0 g. (88% yield) of 4-methylamino-
l-ethyl [192,4]triazolo[4,3-a]quinoxaline, m.p. 271-3C.
Mass spectrum: m/e, 227 (P).
Anal. Calcd. for C12H13Ns 1/8~I20 C~
H, 5.82; N, 30.51.
Found: C, 62.72; H, 5.86; N, 30.62.
Example ]6
4-Dimethylamino-l-ethyl[1,2,4]triazolo[4,3-a]guinoxaline
4-Chloro-l-ethyl-[1,2,4]triazolo-[4,3-a]quinoxaline
~1.2 g., 0.005 mole), the product of Example 4, and 676
mg. (0.015 mole) of anhydrous dimethylamine in N,N-dimethyl-
formamide (50 ml.) were stirred at 0C, for 30 minutes and
at room temperature for 2 hours. The reactisn mixture
was poured over ice and stirred for 20 minu~es.
The precipitate which formed was separated by filtration,
washed with water and air dried. Recrystallization
from chloroform and then from chloroform/cyclohexane
afforded 510 mg. (42% yield) of 4-dimethylamino-1-
ethyl-[1,2,4]triazolo[4,3-a]quinoxaline, m.p. 155-8Co
Mass spectrum: m/e, 241 (P).
Anal. Calcd. for C13H15N5: C, 64.71; H, 6.27; N, 29.02.
Found: C, 64.69; H, 6.27; N, 29.32.
-38
f ~ 2
Example 1-7
- l-Ethyl-4-ethylamino-[1,2,4]triazolo[4,3-a]quinoxaline
Monoethylamine was bubbled through a solution o
4~chloro-1-e~hyl-[1,2,4]triazolo[4,3-a]quinoxaline
(1~2 g., 0.005 mole), the product of Example 4, in N~N-
dimethylformamide (50 ml.) at 0C. for about 2 minutes.
The clear solution was stirred at 0C. for 30 minutes and
at room temperature or 2 hours. The reaction mixture was
next poured over ice and the precipitate was separated
by filtration, washed with water and air dried.
Recrystallization from ethanol then afforded 1.0 g, (83%
yield) of pure l-ethyl-4-ethylamino-[1,2,4]triazolo[4,3-a]
quinoxaline as a white solid ~m.p. 235-238C.).
Mass spectrum m/e, 241 (P).
nal. Calcd. for C13H15N5: C, 64~71; H, 6.27; N, 29-02-
Found: C, 64.57; H, 6,20; N, 29.15.
Example 18
4-Diethylamino-l-ethyl-~1,2,4~triazolo[4,3-a]quinoxaline
This compound was prepared by the method of
Example 11, utilizing 4-chloro-1-ethyl-[1,2,4]triazolo-
[4,3-a]quinoxaline (the product of Example 4) as starting
material in place of 4-chloro-[1,2,4]triazolo[4,3-a]-
quinoxaline tthe product of Example 2) and diethylamine as
reagent in place of di-n-propylamine. The crude product
was recrystallized from cyclohexane to afford 3.54 g.
(69% yield) of pure 4-diethylamino-1-ethyl-[1,2,4]triazolo-
[4,3 a]quinoxaline as a white solid (m.p. 98-100C.).
Mass spectrum: m/e, 269 (P).
``` ~LZ~7~72
( i -39-
Exam~le 19
4-Isopropylamino-l-ethyl [1,2,4]triazolo[4,3-a]quinoxaline
Isopropylamine (1.77 g~, 0.03 mole) was added to a
solu~ion of 4-chloro-1-ethyl-[1,2,4]triazolo-[4,3-a~-
quinoxaline (2.3 g., 0.01 mole), ~he product of Example 4,
in N,N-dimethylformamide (30 ml.). Within 30 minutes, a
precipitate formed. The reaction mixture was then stirred
overnight at room temperature. The precipitate was
separated by filtration and washed with N,N-
dimethylformamide. Recrystallization from thanol
then gave 1.6 gO (63% yield) of 4~isopropylamino-1-ethyl
[1,2,4]triazolo[4~3-a]quinoxaline, m.p. 222-4C,
Mass spectrum: m/e, 255 (P).
- Anal. Calcd- for C14H17N5: C9 65.86; H, 6.71; N, 27.43.
Found: C, 65.32; H, 6.76; N~ 27.25.
Example 20
4-Ethylamino-l-isopropyl-[1,2,4]triazolo[4,3-a]quinoxaline
A slurry of 1.0 g. (0.004 mole) of 4-chloro-1-
isopropyl-[1,2,4]triazolo[4~3-a]quinoxaline (the product
of Example 6) in N,N-dimethylformamide (15 ml.) was
saturated with monoethylamine gas and stirred at room
temperature for 4 hours. The precipitate was separated
by filtration and washed with N,N-dimethyl~ormamide to
afford 220 mg. (22% yield) of 4-ethylamino-1-isopropyl-
[1,2,4]triazolo[4,3-a]quinoxaline, m.p. 209-211C.
Mass spectrum: m/e, 255 (P).
-~ -40~ 2
The filtrate was next poured over ice and the
precipitate was separated by means of filtration, washed
with water and recrystallized from methanol and then from
isopropanol to afford another 200 mg. (20% yield)
of pure 4-ethylamino-l-isopropyl-[1,2,4]triazolo[4,3 a]-
quinoxaline, m.p. 210~211C.
Anal. Calcd, for C14H17N5: C, 65.86; H, 6.71; N, 27.43.
Found: C, 65.53; H, 6.58; N, 27.29.
Example 21
4-Diethylamino-l-isopropyl-[1,2~4]triazolo[4,3-a]-
quinoxaline
4-Chloro-l-isopropyl-[1,2,4]-triazolo[4,3-a]quinoxaline
(1.0 g. 9 0.004 mole), the prodwct of Example 6, and 900 mg.
(0.012 mole) of diethylamine in N,N-dimethylformamide
(15 ml.) were stirred at room temperature for 4
hours. The reaction mixture was poured over ice and
the precipitate was separated by means of filtration, washed
with water and placed on a column of silica gel (175 ml.)
and finally eluted with chloroform. The eluant was
evaporated in vacuo to afford 850 mg. (75% yield) of
pure 4-diethylamino-1-isopropyl-~1,2,4]triazolo[4,3-a]-
quinoxa]ine as a white solid (m.p. 93-95C.).
Mass spectrum: m/e, 283 (P). The pure product (100 mg.)
was then distilled in vacuo (0.1 mm) at 140 to 150C.
to afford the analytical sample (80 mg.), m.p. 94-96C.
Anal. Calcd. for C16H21N5: C, 67.82; H, 7.47; N, 24,71.
Found: C, 67.56; H, 7.20; N, 24.50.
4~ 772
Example 22
4~Diethylamino-l-n-propyl-[1,2,4]triaz,olo[4,3-a]-
quinoxaline
4-Chloro-l-n~propyl-[1,2,4J-triazolo[4,3-a~quinoxaline
(1.23 g., 0.005 mole), t~e product of Example 5, and
1.1 g, (0.015 mole) o~ diethylamine in N,N-dimethyl~ormamide
(15 ml.) were stirred at room temperature for 2 hours.
The reaction mixture was then poured ovex ice. ~he
precipitate was removed by filtration, washed with
water and air dried. Recrystallization (twice) from
e~hanol/water afforded 1.1 g. (78% yield) of pure
4-diethylamino-1-n-propyl-[1,2,4]triazolo[4,3-a]-
quinoxaline, m.p. 92-94C. Mass spectrum: m/e, 283 (P).
Anal. Calcd. for C16H21N5 1/8~I2 C~ 67-28;
H, 7.50; N, 24.52.
Found: C, 67.38; H, 7.45; N, 24.73,
Example 23
8-Chloro-4-diethylamino-1-ethyl-[1,2,4]triazolo[4,3-a_
quinoxaline
a) Preparation of 4,8-dichloro-1-ethyl-[1,2,4]triazolo-
[4,3-a]quinoxaline
2,6-Dichloro-3-hydrazinoquinoxaline (1.0 g., 0.0044
mole), the product of Preparation L(a), was refluxed with
15 ml. of triethyl orthopropionate for 4 hours and cooled
to room temperature. The precipitate was recovered by
filtration, washed with cyclohexane and air dried to
afford 730 mg. (62% yield) of 4,8-dichloro-1-ethyl-
[1,2,4]triazolo[4,3-a]quinoxaline, m.p. ~250~C.
Mass spectrum: m/e, 266 (P); m/e, 268 (P+2),
-~2~ 777~
b) Preparation of 8-chloro-4-diethylamino-1-ethyl-
[1,2,4]triazolo-[4,3-a]quinoxaline
4,8-Dichlora-l-ethyl-[1,2,4]triazolo[4,3-a]quinoxaline
(7.4 g., 0.028 mole) and 6 g. (0.082 mole) of diethylamine
in N,N-dimethylformamide (150 ml.) were stirred at room
temperature for 4 hours. The reaction mixture was filtered
and the filtrate was poured over ice. The precipitate
which formed was then collected by means of filtration and
taken up in chloroform. The chloroEorm layer was
subsequently dried over anhydrous magnesium sulfate,
filtered and then evacuated in vacuo to yield an off-white
-
solid which was later recrystallized from diethyl
ether/pe~roleum ether to afford 1.6 g. of pure 8-chloro-4-
diethylamino-l-ethyl[1,2 9 4]triazolo~4,3-a]quinoxaline,
m.p~ 105-108C. (decomp.).
Mass Spectrum: m/e, 303 (P); m/e, 305 ~P~2).
Anal- Calcd- for C15H18ClN5 C, 59.30; ~, 5.97; N~ 23-05-
Found: C, 58.92; H, 5.85; N, 22.81.
7,8-Dichloro-4-diethylamino-1-ethyl-[1,2,43triaæolo-
[4,3-a]quinoxaline
a) Preparation of 2,6,7-Trichloro-3-hydrazino-
quinoxaline
2,3,6,7-Tetrachloroquinoxaline (4.4 g., 0.016 mole)
and 1.76 g. (0.035 mole) of hydrazine hydrate in ethanol
(60 ml.) were stirred overnight at room temperature.
The thick slurry was filtered and washed with ethanol
to afford 4.9 g. of crude 2,6,7-trichloro-3-hydrazino
quinoxaline, m.p. C260C.
Mass spectrum: m/e, 262 (P); m/e, 264 (P~2).
~3~ 7 ~t~2
b) Preparation o~ 4,7,8~Trichloro~l-e-thyl-[1,2,4~-
triazolo[4,3-a~quinoxaline
2,6,7-Trichloro-3-hydrazinoquinoxaline (4.9 g.,
0.018 mole) in triethyl orthopropionate (50 ml.) was
heated at 100C. for 2 hours. The precipitate which formed
was collected by means of fil~ration at room temperature
and washed with cyclohexane. Recrystallization from
chloroform/cyclohexane two times then afforded 2.9 g. (54%
yield) of pure 1,7,8-trichloro-l~ethyl-[1,2,4]triazolo[4,3-a]-
quinoxaline as a pink solid (m.p. 198 201C.~.
Mass spectrum: m/e, 300 (P); m/e, 302 ~P+2); m/e, 304 (P+4);
m/e, 306 (P+6).
c) Preparation of 7,8-dichloro-4-diethylamino-1-ethyl-
[1,2,4]triazolo[4,3a]quinoxaline
497,8-Trichloro-l-ethyl-[1,2~4]-triazolo[4,3-a~-
quinoxaline (2.9 g., 0.0096 mole) and 2.1 g. (0.0388 mole)
of diethylamine in N,N-dime~hylformamide (50 ml.~ were
stirred at room temperature for 2 hours. The reaction
mixture was poured over ice and stirred for 15 minutes.
The precipitate was separated by filtration, washed
with water and air dried. Recrystallization (three times)
from isopropanol then afforded 500 mg. (16% yield) of
pure 7,8-dichloro-4-diethylamino-1-ethyl- ~ 1 7 2,4]triazolo-
[4,3~a~quinoxaline, m.p. 147-149C.
Mass spectrum: m/e, 337 (P); m/e, 33g (P+2).
Anal- Calcd- for C15H17C12N5 C, 53-26; H, 5.07; N, 20.70.
Found: C, 53.05; H, 5.13; N9 20.75.
Example 25
4-Diethylamino-l-ethyl-8-methoxy-[1,2,4]triazolo-
[4,3-a]quinoxaline
a) Preparation of 2-chloro-3-hydrazino-6-methoxy-
quinoxaline
2,3-Dichloro-6-methoxyquinoxaline (4.2 g., 0.018 mole),
the product of Preparation E(b), and 2.7 ml. of hydrazine
hydrate in 100 ml. of ethanol were heated under re~lux for
4 hours and stirred at room temperature overnight. The
44- ~ Z ~
precipitate was removed by iltration and washed with
ethanol ~o afford 3.9 g. (97~ yield) of 2-chloro-3-
hydrazino-6-methoxyquinoxaline, m.p. C250C.
Mass spectrum: m/e, 224 (P); m/e 226 (P-~2).
S b) Preparation of 4-chloro-l-ethyl-8-me~hoxy-~1,274]-
triazolo[4,3-a]quinoxaline
2-Chloro~3-hydrazino~6-methoxyquinoxaline (1.3 g.,
0.0058 mole) and 25 ml. of triethyl orthopropionate were
heated at 100C. for 4 hours and stirred at room
temperature for 60 hours. The precipitate was
removed by filtration and washed with ethanol.
Recrystallization from ethanol then afforded 530 mg. (35%
yield) of pure 4-chloro 1-ethyl-8-methoxy-[1,2,4]triazolo-
[4,3-a]quinoxaline, m.p. 196-198C. (decomp.).
Mass spectrum: m/e, 262 (P); m/e 264 (P~2).
c) Preparation of 4-diethylamino-1-ethyl-8-methoxy-
[1,2,4]triazolo[4,3-a]quinoxaline
4-Chloro-l-ethyl-8-methoxy-~1,2,4]~riazolo[4,3-a]-
quinoxaline (520 mg., 0.002 mole) and 673 mg. (0.008
mole) of diethylamine in 10 ml. of N,N-dimethylformamide
were stirred at room temperature overnight. The
reaction mixture was poured over ice and the precipitate
was separated by filtration, washed with water and
air dried. Recrystallization from diethyl ether and
petroleum ether then afforded 140 mg. (23% yield) of
pure 4-diethylamino-1-ethyl-8-methoxy [1,2,4]triazolo-
[4,3-a]quinoxaline, m.p. 135-138C.
Mass spectrum: m/e, 299 (P)
Anal. Calcd. for C16H21N5O 1/8H2O:
H, 7.10; N, 23.22.
Found: C, 63.63; H, 6.88; N, 23.37.
~ 5 ~7~7~
Example 26
4-Diethylamino-l-phenyl-[1,2,4]triazolo[423-a]quinoxaline
a) Preparation of 4-chloro-1-phenyl-[1,2,4]triazolo-
[4,3-a]quinoxaline
2-Chloro 3-hydrazinoquinoxaline (2.2 g., 0.011 mole)
was mixed with 6 ml. of triethyl orthobenzoate and heated
at 100C. for 30 minutes. After cooling the orange
mixture to room temperature, ethanol was added.
Filtration of the resultant precipitate afforded 2.1 g.
of crude product which was further purified by means of
trituration with warm methanol, followed by filtration
and air drying to ultimately yield 1.58 g. (51%) of pure
4-chloro-1-phenyl-[1,2,4]triazolo[4,3-a]quinoxaline as
an orange solid.
b) Preparation of 4-diethylamino-1-phenyl-[1,2,4]triazolo-
[4,3-a]quinoxaline
To 1.58 g. (0.00563 mole) of 4-chloro-1-phenyl-[1,2,4]-
triazolo[4,3-a]quinoxaline dissolved in 15 ml. of N,N-dimethyl-
formamide1 there was added 1.738 mlO of diethylamine. The
mixture was stirred overnight at room temperature.
The precipitate which formed was collected by filtration,
washed with N,N-dimethylformamide and recrystallized two
times from hexane/ethyl acetate (3:1 by volume) to afford
555 mg. of pure 4-diethylamino-1-phenyl-[1,2,4]triazolo[4,3~a]-
quinoxaline in the form of white needles (m.p. 166-168C.)
Anal. Calcd. for ClgHlgN5: C, 71.60; H, 5.99; N, 22.06.
Found: C~ 71.86; H, 5.86; N, 22.09.
~ -46- ~Z~7~
Example 27
4~Diethylamino~l-tri1uoromethyl-[1,2,4]triazolo[4~3-a]-
quinoxaline
A) Preparation of 4~hydroxy-1-trifluoromethyl-[1,2,4]-
triazolo[4,3-a]quinoxaline
2-Chloro-3-hydrazinoquinoxaline (3.89 g., 0.02 mole~,
the product of Example 1, is added to 22.3 g. (0.20 mole)
of cold trifluoroacetic acid (15.4 ml.) contained in a
flame-dried reaction ~lask surrounded by an ice bath,
while under a dry nitrogen atmosphere with the aid of
mechanical stirring7 The reaction mixture was then
heated to 100C. for a period of 3 hours and poured
over ice. The resulting product was then collected by
means of suction filtration, washed with water and air
dried to constan~ weight~ In this manner, there were
ultimately obtained 3 0 g. (60%) of pure 4-hydroxy-1-
trifluoromethyl-[1,2,4]triazolo[493-a]quinoxaline,
m.p ~300C. Mass spectrum: m/e, 254(P)
b) Preparation of 4-chloro-1-trifluoromethyl-
~1,2,4]tria~olo[4,3-a]quinoxaline
In a flame-dried reaction flask under a dry nitrogen
atmosphere, ~her~ wer~ placed 3.0 g. (0.0118 mole) of
4-hydroxy-1-trifluoromethyl-[1,2,4]triazolo[4,3-a]-
quinoxaline and 30 ml. of phosphorus oxychloride in
2.38 g. (~.0236 mole) of triethylamine (3.3 ml.). The
reaction mixture was then heated at 100C. for a period
of approximately 16 hours (i.e., overnight). Upon com-
pletion of this step, the spent mixture was cooled to
room temperature, concentrated in vacuo and then
partitioned between ice, water and ethanol, ~ollowed by
extraction with ethyl acetate. The latter extract was
next washed with saturaeed brine and dried over anhydrous
magnesium sulfate. After removal of the drying agent by
means o-f filtration and the solvent by means of evaporation
-47-
under reduced pressure, there was obtained a residue
which was subsequently dissolved in hot chloroform and
filtered. The latter filtrate was then allowed to stand
overnight at room temperature and filtered again. The
final filtrate was then concentrated in vacuo to
ultimately afford 1.4 g. of 4-chloro-1-trifluoromethyl
[1,2,4]triazolo[4,3-a]quinoxaline in the form of a
brownish-colored solid.
c) Preparation of 4-diethylamino-1-trifluoromethyl
[1,2,4]triazolo[4,3-a]quinoxaline
A mixture consisting of 700 mg. (0.0025 mole) of
4-chloro-1-trifluoromethyl-[1,2,4]triazolo[4,3-a]-
quinoxaline (prepared as described above) and 560 mg.
(0.0075 mole) of diethylamine (0.8 ml.) in 10 ml. of
N,N-dimethylformamide was stirred at room temperature
overnight and then poured over ice. The resulting
mixture was then filtered and the recovered solid
product washed with water and then dissolved in ethyl
acetate. The latter organic solution was next wash~d
with saturated brine and dried over anhydrous
magnesium sulfate. After removal of the drying agent
by means of filtration and the solvent by means of
evaporation under reduced pressure, there was ultimately
obtained a light yellow solid which after recrystalli-
zation from diethyl ether gave pure 4-diethylamino-1-
trifluoromethyl-[1,2,4]triazolo[4,3-a]quinoxaline.
The yield of the first crop mel~ing at 155-157C.
amounted to 260 mg. (34Z), while the yield of the
~ second crop melting at 153-156C amounted to 170 mg.
(22%).
Anal- Calcd- for C14H14F3N5 C~54-37; H~ 4-56;
N9 22.64.
Found: C, 54.08; H, 4.47; N, 23.32.
77~2
Example 28
4-lsopropylamino-l-trifluoromethyl-[1,2,4]triazolo-
[4,3-a]quinoxaline
A mixture consisting of 700 mg. (0.0025 mole) of
4-chloro-1-tri~luoromethyl [1,2,4]triazolo[4,3-a]quinoxaline
tthe product of Example 27b) and 443 mg. (0.0075 mole)
of isopropylamine (0.64 ml.) in 10 ml. of N,N-dimethyl-
formamide was stirred at room temperature overnight
and then poured over ice. The resulting mixture was
then filtered and the recovered solid product washed
with water and then dissolved in diethyl ether. The
latter ethereal solution was next washed with saturated
brine and dried over anhydrous magnesium sulfate.
After removal o~ the drying agent by means of filtration
and the solvent by means of evaporation under reduced
pressure, there was ultimately obtained a white solid
powder which after one recrystallization from diethyl
ether yielded 550 mg. (74%) of pure 4-isopropylamino-
l-trifluoromethyl-[1,2,4]triazolo[4,3-a]quinoxaline,
m p. 185-187C.
Anal. Calcd. for C13H12F3N5: C7 52-88; H~ 4-10;
N, 23.72.
Found: C, 52~73; H, 4.00; N, 23.67.
~ 9 ~L z~7r7~7Z
~ 29
l-Ethyl-4-(N-ethylacetylamino)-[1,2,4]triazolo~4,3-a]-
quinoxaline
A mixture consisting of 241 mg. (0.001 mole) o~
1-ethyl-4-ethylamino-[1,2,4]triazolo[4,3-a]quinoxaline
(the product of Example 17) and 2,5 g, ~0.025 mole)
of acetic anhydride (2.5 ml.) contained in a flame-
dried reaction flask was refluxed tl40C.) under a
dry nitrogen atmosphere for a period of three hours and
then allowed to cool to room temperature. At this
point, a precipitate formed and the resulting reaction
mixture was poured into water and then extracted
with chloroform. The chloroform extracts were combined,
washed with water and subsequently dried over anhydrous
magnesium sulfate. After removal of the drying agent
by means of filtration and the solvent by means of
evaporation under reduced pressure, there was obtained
a solid product which after one recrystallization from
chloroform/diethyl ether afforded 160 mg, (57~) of
1-ethyl-4-(N-ethylacetylamino3 1j2,4-triazolo[4,3-a]-
quinoxaline, m.p, 185-187C.
Anal-Calcd- for C15H17N5 C, 63.59; H~ 6-05;
N 9 24.72.
Found: C, 63.17; H, 6.05; N, 24.39.
~50-
Example 30
4-Acetylamino-l-ethyl-[1,2,4]triazolo[4,3~a~quinoxaline
A mixture consisting of 533 mg. (0.0025 mole) of
4-amino 1-ethyl-[1,2,4]triazolo[4,3-a]quinoxaline (the
product of Example 14) and 1.0 g. (0.01 mole) o~ acetic
anhydride (1.0 ml.) in 20 ml. of methylene chloride
was refluxed overnight (~J16 hours) and then allowed to
cool to room temperature~ The resulting clear solution
was then concentrated in vacuo to afford a white solid
substance that was subsequently recrystallized from
chloroform/diethyl ether to yield 520 mg, (82%) of
pure 4-acetylamino-1-ethyl-~1,2,4]triazolo[4,3-a]-
quinoxaline, m.p~ 193-195C.
Anal. Calcd. For C13H13N5O: C9 61-16; H~ 5-13;
N, 27.43.
Found: C, 60.90; H, 5.26; N, 27.66.
- ~ f ~ ~J~3
7 ~ ~
51-
Example 31
4-Diacetylamino-l-ethyl-[1,2,4]triazolo~4,3-a]-
quinoxaline
A mixture consisting of 5 5 g. (000258 mole) of
4-amino-1-ethyl-[1,2,4]triazolo[4,3-a]quinoxaline (the
produc~ of Example 14) and 25 g. (0.25 mole) o~ acetic
anhydride (25 ml.) in 60 ml. o pyridine containing
100 mg. of ~-dimethylaminopyridine was stirred at room
temperature overnight (~J18 hours). The resulting slurry
was then filtered to remove the insolubles and the orange-
red filtrate was therea~ter evaporated under a high
vacuum to give a dark gummy residue. Upon the addition
of water, pinkish-white crystals were obtained and
these were subsequently collected by means of suction
filtration, washed with a copious amount of water and
dried in vacuo at 50C. to ultimately afford 2.9 g,
(38%) of 4-diacetylamino-1-ethyl-[1,2,4]triazolo-
[493-a]quinoxaline, m.p. 157-159C. Recrystallization of
the latter material from ethyl acetate/diethyl ether
then gave an analytically pure sample ~m.p. 158-160C).
The pure product was further characterized by means of
mass spectroscopy and nuclear magnetic resonance data,
in addition to elemental analysis. Mass spectrum: m/e,
297(P)~
~5 Anal. Calcd- for ClsH15NsO2 C~
N,23.56.
Found: C, 60.33; H, 5.09; N, 23.41.
- 52 -
B77'~'2
Example 32
The following [1,2,4]triazolo[4,3-a]quinoxaline-4-amine
derivatives were prepared by employin~ the procedures descxibed
in the previous preparations and examples, starting from readily
available materials in each instance
7,8-dibromo-4-diethylamino- [1,2,4]triazolo[4,3-a)-
quinoxaline, m.p. 199-201C.
8-chloro-4-isopropylamino-[1,2,4]triazolo[4,3-a]-
quinoxaline, m.p. 177-181C.
4-ethylamino-1-trifluoromethyl-[1,2,4]triazolo-
[4,3-a]quinoxaline, m.p. 223-225C.
l-ethyl-4-ethylamino~8-me-thoxy-[1,2,4]triazolo[4,3-a]-
quinoxaline, m.p. 234-237C~
4-diethylamino-8-methoxy-[1,2,4]triazolo[4,3-a]-
quinoxaline, m.p. 124-126C.
8-chloro-1-ethyl-4-isopropylamino-[1,2,4]triazolo-
[4,3-a]quinoxaline, m.p. 189-191C.
4-(N-plperazine)-[1,2,4]triazolo[4,3 ~quinoxaline,
m.p. 160-162C.
8-chloro-4-(N-piperazino)-[1,2,4]triazolo[4,3-a]-
quinoxaline, m.p. 253-256C.
8-chloro-4-(N~isopropylacetylamino)-[1,2,4]triazolo
[4,3-a]quinoxalinQ, m.p. 148-151C.
4-acetylamino-8-chloro-1 ethyl-[1,2,4]triazolo-[4,3-a]
quinoxaline, m.p. 203-205C.
8-chloro-1-ethyl-4-(N isopropylacetylamino)[l,2,4
triazolo[4,3-a]quinoxaline, m.p. 155-158C.
~.
- 52a _ ~ ~v7 7~2
7,8-dichloro-4-(N-isopropylacetylamino)-[1,2,4]-
triazolo~4,3-a]quinoxaline, m.p. 207-210C.
4-amino-7,8-dichloro-1-ethyl-1[1,2,4]triazolo[4.3-a]-
quinoxaline, m.p. > 260C.
4-amino-8-chloro~l-ethyl-[1,2,4]triazolo[4,3-a]-
quinoxaline, m.p. 248-253C.
4-acetylamino-7,8-dichloro-1-ethyl- [1,2,4]triazolo-
~4,3-a]quinoxaline, m.p. 230-232C.
8-fluoro-4-isopropylamino-[1,2,4]triazolo[4,3-a]-
quinoxaline m.p. 215-217C.
~,,
~ -53- ~Z~7~
4-ethylamino-8-fluoro-[1,2,~]triazolo[4,3-a]quin-
oxaline, m.p. 239-242C.
l-ethyl 8-fluoro-4-isopropylamino-[1,2,4]triazolo-
[4,3-a]quinoxaline, m.p. 209-212C.
7,8-difluoro-4-isopropylamino ~1,2,4]triazolo[4,3-a]-
quinoxaline, m.p. 218-221C.
l-ethyl-4-ethylamino-8-fluoro-[1,2,4]-triazolo[4,3-a]-
quinoxaline, m.p. 231-233C.
7,8-difluoro-4-ethylamino-[1,2,4]triazolo[4,3-a]-
quinoxaline, m.p. 208-211C.
4-diethylamino-8-fluoro-~192,4]triazolo[4,3-a]quin
o~aline, m.p. 151-153C.
4-diethylamino-l-ethyl-8~luoro-[1,294]triazolo-
[4,3-a]quinoxaline, m.p. 94-97C.
7-chloro-4-dimethylamino-1-ethyl-[1,2,4]triazolo-
[4,3~a]quinoxaline methanesulfonate (mesylate), m.p.
214-217C.
7-chloro-4-diethylamino 1-ethyl-[1,2,4~triazoloL4,3-a]-
quinoxaline methanesul~onate9 m.p. 172-175C.
7,8-dichloro-1-ethyl-4-(N-piperazino) [192,4]triazolo-
[4,3-a]quinoxaline methanesulfonate, m.p. 252-255C.
7~8-dichloro-4-dimethylamino-1-ethyl-[1,2,4]triazolo-
[4,3-aJquinoxaline; m.p. 168-171C.
7,8-dichloro-4-dimethylamino-1-ethyl-[1,2,4]tria-
zolo[4,3-a]quinoxaline methanesul~onate, m.p. 216-219C.
4-acetylamino-l~ethyl-8-fluoro-[1,2,4]triazolo-
[4,3-a]quinoxaline, m.p. 203-205C.
4-amino-7-chloro-1-ethyl-~1,2,4]triazolo[4,3-a]-
quinoxaline methanesulfonate, m.p. 240-243C.
7-chloro-1-ethyl-4 ethylamino [1,2,4]triazolo[4,3-a]~
quinoxaline methanesulfonate, m.p. 187-189C.
7-chloro-4-diethylamino-[1,2,4]triazolo[4,3-a~-
quinoxaline methanesulfonate, m.p. 205-207C.
4-diethylamino-7,8-difluoro-[1,2,4]triazolo[4,3-a]-
quinoxaline methanesulfonate, m.p. 220-223C.
4-acetylamino-7-chloro-1-ethyl-[1,2,4]triazolo-
[4,3-a]quinoxaline, m.p. 210-212C~
~ -5~ 7 ~ ~
~, J
8-chloro-1 e~hyl-4-ethylamino-[1,2,4]triazolo[4)3~a]-
quinoxaline methanesulfonate, m.p. 235-238C.
4-amino-7-chloro-[1,2,4]triazolo[4,3-a]quinoxaline
methanesulfonate, m.p. 279-282C.
54-amino-8-chloro-1-methyl-[1,2,4]triazolo[4,3-a]-
quinoxaline methanesulfonate, m.p. 213-215C.
8-chloro-4-isopropylamino 1-trifluoromethyl-[1,2,4]-
triazolo[4,3-a]quinoxaline me-thanesulfonate, m.p. 183-185C.
8-chloro-4-die~hylamino-1-methyl-[1,2,4]~riazolo-
10[4,3-a]quinoxaline methanesulfonate, m.p. 172-175C.
4-diacetylamino-[1,2,4]triazolo[4,3-a]quinoxaline,
214C.
4-diacetylamino-8-chloro-[1,2,4]triazolo[4 7 3-a]-
quinoxaline, m.p. 208-210C.
158-chloro-4-isopropylamino~l-methyl-[1,2,4]triazolo-
[4,3-a]quinoxaline methanesulfonate, m p. 206-208C.
4-acetylamino-1-methyl-8-chloro-~1,2,4]triazolo
[4,3-a~quinoxaline, m.p. 262-264C.
8-chloro-1-ethyl-4-trimethyla~etylamino-[1,2,4]-
20triazolo[4,3-a]quinoxaline, m.p. 211-213C.
7,8-difluoro-1-ethyl-4-isopropylamino-[1,2,4]tria-
zolo[4,3-a]quinoxaline methanesulfonate, m.p. 151-152C.
4-n-butyrylamino-8-chloro-1-ethyl-[1,2,4]triazolo
[4,3 a3quinoxaline, m.p. 185-187C.
258-chloro-4-diethylamino-1-trifluoromethyl-[1,2,4~-
triazolo[4,3-a]quinoxaline hydrate, m.p. 135-136C.
4-amino-8-chloro-1-trifluoromethyl-[1,2,4]triazolo-
[4,3 a3quinoxaline methanesulfonate, m.p. 259-261C.
4-ethylamino-8-fluoro-1-trifluoromethyl-~1~2,4]-
30triazolo[4,3-a]quinoxaline methanesulfonate, m.p 180-183C.
8-fluoro-4-isopropylamino-1-trifluoromethyl-[1,2,4]-
triazolo~4,3-a]quinoxaline methanesulfonate, m.p. 185-188C.
4-diethylamino-7,8-difluoro-1-ethyl-[1,2,4]triazolo-
[4,3-a]quinoxaline, m.p. 109-111C.
351-ethyl-4-ethylamino-7-fluoro-[1,2,4]triazolo[4,3-a]-
quinoxaline methanesulfonate, m.p, 215-219C.
55 -
4-amino-7-methoxy-[1,2,4]triazolo[4,3-a]quinoxaline
methanesul~onate, m.p. 262-264C.
8-chloro-4-isopropylamino-1--phenyl-[1,2,4]triazolo-
[4,3-a]quinoxaline, m.p. 183-186C.
8-chloro-4-ethylamino-1-phenyl-[1,2,4]~riazolo-
[4,3-a]quinoxaline, m.p. 254-256C.
7-fluoro-4-isopropylamino[1,2,4]triazolo~4,3-a]-
quinoxaline methanesulfonate, m.p. 214-216C.
4-ethylamino-7-fluoro-[1,2,4]triazolo[4,3-a]quinox-
aline methanesulfonate, m.p. 216-218C.
4-diethylamino-8-fluoro-1-trlfluoromethyl-[1,2,4]-
triazolo[4,3-a]quinoxaline, m.p. 146-149Co
7,8-dichloro-1-ethyl-4-isopropylamino-[1,2,4]triazolo-
[4,3-a]quinoxaline, m.p. 197-198C.
8-chloro-4-diethylamino-1-phenyl-[1,2,4]triazolo-
[4,3-a~quinoxaline, m.p. 194-195C.
4-acetylamino-1-ethyl-7-fluoro-[1,2,4]triazolo[4,3-a]-
quinoxaline, m.p. 273-275~C.
4-acetylamino-8-chloro-1-trifluoromethyl-[1,2,4]tria-
zolo~4,3-a]quinoxaline, m.p. 215-216C.
4-amino-8~chloro-1-phenyl-[1,2,4]triazolo[4,3-a]-
quinoxaline methanesulfonate, m.p. 273-275C~
8-chloro-4-ethylamino-1-trifluoromethyl-[1,2,4]-
triazolo[4,3-a]quinoxaline, m.p. 228-230C.
l-ethyl-7-fluoro-4-isopropylamino-[1,2,4~triazolo-
[4,3-a]quinoxaline methanesulfonate, m.p. 178-181C.
- 55a - ~Z~777z
4-amino-8-fluoro-1 trifluoromethyl-[1,2,4]triazolo-
[4,3-a]quinoxaline hydrate, m.p. 260-263C.
8-chloro-1-ethyl-4R-phenylisopropylamino-~1,2,4]-
triazolo[4,3-a]quinoxaline, m.p. 155-157C.
4~amino-1-ethyl-7-fluoro-[1,2,4Jtriazolo[4,3-a]-
quinoxaline, m.p. 285-289C.
4-amino-1-ethyl-7-methoxy-[1,2,4]triazolo[4,3-a]-
quinoxaline methanesulfonate, m.p. 255-258C.
4-acetylamino-8-fluoro-1-trifluoromethyl-[1,2,4]-
triazolo[4,3-a]quinoxaline, m.p. 217-219C.
s
~.,
1 - 56 -
7~72
4-acetylamino-1-ethyl-7-methoxy-[1,2,4]triazolo-
[4,3-a]quinoxaline, m.p. 202-205C.
8-chloro-1-ethyl-4S-phenylisopropylamino-[1,2,4]-
triazolo[4,3-a] quinoxaline m.p. 156-157C.
4-acetylamino~8-fluoro-[1,2,4]triazolo[4,3-a]-quinox-
aline, m.p. 240-242C.
4-acetylamino-[1,2,4]triazolo[4,3-a]quinoxaline, m.p.
269-272C.
4-amino-7-fluoro-[1,2,4~triazolo[4,3-a3quinoxaline
methanesulfonate, m.p. 246-248C.
4-amino-8-fluoro-[1,2,4]triazolo[4,3-a]quinoxaline
methanesulfonate, m.p. 176-178C.
4-acetylamino-7-fluoro-[1,2,4]triazolo[4,3-a]quinoxaline,
m.p. 290-292C.
8-chloro-4-isopropylamino-1-pentafluoroethyl- [1,2,4]
triazolo[4,3-a]quinoxaline, m.p. 171 174C.
Example 33
8-Chloro-l-ethyl-4-propionylamino-[1,2,4]triazolo[4,3-a]-
quinoxaline
A mixtuxe consisting of 1.25 g. (0.005 mole) of 4-amino-
3~chloro-1-ethyl-[1,2,4]triazolo[4,3-ajquinoxaline (m.p. 248-253
C), a product reported in Example 32, and 15 mlO of propionic
anhydride was refluxed overnight for a period of approxima-tely 16
hours and then cooled to room temperature t~ 20C.). Upon
completion of this step, the resulting reaction mixture was
filtered and the recovered precipitate was subsequently dissolved
.~
` - 56a -
Z~777Z
in chloroform. The latter organic solution was then filtered
and therea:Eter successively washed with water, saturated aqueous
sodium bicarbonate solution and saturated brine, followed by
drying over anhydrous magnesium sulfate. After removal of the
drying agent by means of filtration and the solvent by means oE
evaporation under reduced pressure, there was obtained a residual
material
.~. ...
~ 57_ ~ 77~
that ~as subsequently chromatographed on a 150 ml. silica
gel column and then eluted with chloroform/methanol
(95:5 by volume). Like fractions containing the product
were combined and thereafter concentrated in ~acuo to
yield a crystalline material, which was later recrystal-
lized from chloroform/ethyl ether to ultimately afford
540 mg. (36Z) of pure 8-chloro-1-ethyl-4-propionylamino-
[lS2,4]triazolo[4,3-a]quinoxaline, m.p. 212-215C.
Anal. Calcd~ for C14H14ClN5 55~36; H~ 4-64; N~ 23-06
Found: C, 54.91; H, 4.59; N9 22.76.
