JPH039915B2 - - Google Patents

Description

[Detailed description of the invention] The present invention is useful as an anti-depressant and anti-fatigue agent.
A series of new [1, 2, 4] triazolo [4, 3]
-a] Quinoxaline-4-amine derivatives and pharmaceuticals
related to their acid addition salts, suitable as Alleviates symptoms of depression and fatigue in snails.
There has been intensive search for effective drugs for
It's here. US Patent No. 3839569 and West German Patent No. 2249350
Among them are triazolo[4,3-a]quinoxalines.
has been described for use as an agricultural pesticide.
Ru. U.S. Patent No. 4008322 describes the plant pathogenic fungus pylori
Caused by Piricularia oryzae
A series of triazolo [4,
3-a] Describe the usage of quinoxaline derivatives
There is. The present invention is useful as an antidepressant and antifatigue agent.
New [1,2,4] triazolo [4,3-
a] Related to quinoxaline-4-amine derivatives
Ru. In particular, the compounds of the invention have the formula: (X and X in the formula¹are hydrogen, fluorine, and chlorine, respectively.
selected from the group consisting of lor, bromo and methoxy.
things; R₁is hydrogen, lower alkyl, lower perfluoro
Alkyl and phenyl; R₂and R₃are hydrogen, lower alkyl, and alkyl, respectively.
Phenylalkyl, carbon with up to 3 carbon atoms
Alkanoyl number 2 to 5; X and X¹are each hydrogen,
R₁If is hydrogen or methyl, R₂and R₃with a little of
One is always something other than hydrogen; R₂and R₃
When they combine with each other, they form a piperazino ring.
Ru. ). Lower-level abbreviations used in claims and details of invention
Alkyl represents alkyl having 1 to 4 carbon atoms,
Lower perfluoroalkyl means, for example, trifluoro
Carbon numbers such as methyl and pentafluoroethyl
Represents 1 to 4 perfluoroalkyl. An important group of compounds of the invention are X and¹but
Hydrogen, R respectively₁is hydrogen, R₂and R₃are each lower alki
It is a compound of A good compound is R₂and R₃
are both ethyl compounds. Other groups of compounds of the invention are X and¹are each water
Basic, R₁is ethyl, R₃is a lower alkyl compound
Yes, a good compound is R₂is hydrogen, R₃is ethyl
It is a compound of Furthermore, other groups of compounds of the present invention include X and¹but
Hydrogen, R respectively₁is lower alkyl, R₃is acetyl
compound, and a good compound is R₁is ethyl, R₂
is a compound of hydrogen, ethyl or acetyl. Further important groups of compounds of the present invention are X and
X¹At least one of them is fluor, R₁is hydrogen or
Rifluoromethyl, R₂is hydrogen, R₃is hydrogen, low grade
Compound of alkyl, alkanoyl having 2 to 5 carbon atoms
thing or X and X¹At least one of them is Kroll,
R₁is lower alkyl, trifluoromethyl, R₂but
Hydrogen, R₃is hydrogen, lower alkyl or carbon number 2~
It is a compound of alkanoyl No. 5. Most new compounds with formulas are shown in reaction diagrams.
It can be produced through a reaction process. Folds in process diagrams
The numbers of the enyl ring and the two heterocycles are as follows:
used throughout. In the process diagram, X and¹are hydrogen and fluoride, respectively.
Luol, chlor, bromo, or methoxy mushroom
sarin derivatives, (in this case the benzene ring is mono-positioned)
(X is always hydrogen), with 1 to 1 carbon atoms
3, such as an alkanol (ethanol is preferred)
reaction of an excess of hydrazide in an inert organic solvent.
react with hydrate for about 18 to 24 hours at room temperature.
Producing an intermediate of formula Intermediate compound of formula
, then the appropriate alkyl orthoalkanoe
or alkyl orthobenzoate and optionally
React at about 80 to 120°C for about 1 to 24 hours,
R₁is the corresponding formula other than lower perfluoroalkyl
Convert to intermediate A. Production of formula A
In the compound, R₁is the specific ortho used in manufacturing.
By alkanoate (as hydrogen or alkyl)
) determined. For example, triethyl orthoform
Using mate R₁is hydrogen, triethylortho
With propionate propionate, R₁Hae
using triethyl orthoisobutyrate
and R₁is isopropyl. Intermediate compounds of formula also include excess equivalents of triflic
such as oroacetic acid or pentafluoropropionic acid.
perfluoroalkanoic acid and, if necessary,
React according to the conventional method, R₁is perfluorinated
Intermediates of formula A corresponding to alkyl, 4-hydro
xy-1-perfluoroalkyl-[1,2,4]
Conversion to triazolo-[4,3-a]quinoxaline
do. This compound is then added to a compound such as triethylamine.
By heating with phosphorus oxychloride in the presence of a tertiary amine
The reaction yields the corresponding 4-chloro compound. Intermediate A(R₁is hydrogen, lower alkyl, lower
(fluoroalkyl or phenyl) in excess formula
HNR₂R₃reacts with an amine in an inert organic solvent (N,
N-dimethylformamide is preferred), about 0 to 60
React at ℃ for about 2 to 24 hours, and R₂and R₃are each
Other than alkanoyl, as defined above
[1,2,4]triazolo[4,3-] of formula A
a] Conversion to quinoxaline-4-amine derivative
Ru. For example R₂and R₃Formula A where both are ethyl
A good compound of formula A is a suitable compound of formula A.
Diethylamine in N,N-dimethylformamide
It is produced by reacting with the compound for 2 to 3 hours at room temperature. similar
niR₂is hydrogen, R₃A good compound of ethyl is the formula
Compound A was dissolved in N,N-dimethylformamide.
React with noethylamine at room temperature for 4 to 5 hours.
Manufactured by R₂and R₃At least one of them has 2 or more carbon atoms
[1,2,4] of formula A which is alkanoyl of 5
Triazolo[4,3-a]quinoxaline-4-a
The min derivative is R₂and R₃At least one of them is hydrogen
A corresponding compound of formula A under anhydrous conditions as appropriate
It is produced by reacting with alkanoic acid anhydride.
Ru. This reaction uses an organic base such as a tertiary amine as a catalyst.
(A catalyst is absolutely necessary, so
(No)) Perform at approximately 20 to 140℃ for approximately 30 minutes to 24 hours. 4
- The equivalent ratio of acid anhydride to amino starting material is small.
at least about 1:1, preferably about 4:1 to 25:1.
Ru. On the other hand, the amount of tertiary amine used is generally
about 25-150% of the weight of the acylating agent. (Tertiary
The amine should be used in excess as a reaction solvent.
). Reactions can be carried out without using solvents
In some cases, it is very good, but in some cases it is moderate.
The use of reaction-inert organic solvents is recommended where indicated.
There are also cases. Suitable organic solvents used here are:
Acetone, methyl ethyl ketone, benzene, tolu
Ene, xylene, dioxane, tetrahydrofura
methylene chloride, chloroform, ethylene
dichloride, tetrachloroethane, methiacetate
ethyl acetate, isopropyl acetate, propion
Methyl acid, ethyl propionate, diethyl ether
diisopropyl ether, di-n-propyl
A neutral, reactive, anhydrous organic solvent such as ether.
Ru. However, as mentioned above, too much acid anhydride
By using this method, you can avoid using such solvents.
Perform a reaction. Similarly, use too much tertiary amine reagent.
It can also be used as a solvent. solvent and/or catalyst
As such, the preferred tertiary amine used in this reaction is tri-
Ethylamine, dimethylaniline, pyridine, pyridine
Choline, lutidine, collidine and quinoline.
Ru. X and X¹The starting materials for the formula where are each hydrogen are
Well known to those skilled in the art. X¹is methoxy
A compound with the formula is G.W.H.Cheeseman's
Manufactured according to the Act [J.Chem.Soc., p.1170 (1962)].
come. Here, 4-methoxy-o−Fenirange
Amine hydrochloride contains at least an equivalent amount of diethyloxa
diethylamine and inert gas (nitrogen)
(preferably a gas) at reflux temperature for about 2 to 3 hours.
followed by a tertiary amine (dimethylaniline is preferred).
Suitable) Incubate with medium phosphorus oxychloride for 1 to 2 hours at reflux temperature.
I will respond. In the reaction process diagram, X is fluor, chloro,
Brome, methoxy, X¹Kino of the formula where is hydrogen
Sodium xaline derivative in alcoholic solvent
methoxide, and slightly warmed (e.g. 40-60
°C) for 6 to 18 hours, the corresponding formula 2
-Production of chloro-3-methoxyquinoxaline derivatives
Build. Next, as before, hydrazine hydrate
2-hydrazino of the corresponding formula
-Producing a 3-methoxyquinoxaline derivative.
This intermediate () is then converted into an appropriate orthoes
or perfluoroalkanoic acid as above.
Therefore, the 7-substituted 4-methoxy of the reaction formula
[1,2,4] triazolo-[4,3-a] mushroom
Produce sarin derivatives and sequentially apply them using conventional methods.
Corresponding 4-hydroxy (formula) and 4-chlor
compound, where X is defined above
(i.e. other than hydrogen), X¹Structural formula where is hydrogen
Compound B is produced. Next, the intermediate of formula B is
Using the method described in the final step of the reaction process diagram
Te, R¹,R²and R³is defined above,
X and X¹The corresponding expression is as above
A new final product of B is obtained. Pharmaceutically suitable acids in novel compounds of formula
Addition salts are also within the scope of this invention. These salts are
Mineral or organic acids and aqueous solutions, suitable as free salts.
Or it can be easily produced by reacting in an organic solvent.
I can do it. Obtaining a solid salt by precipitation or solvent evaporation
I can do it. Acid addition salts suitable as pharmaceuticals of the present invention are
Although not particularly limited, hydrochloride, sulfate,
Bisulfate, mesylate, tosylate, nitrate, lysate
phosphate, acetate, lactate, malate, fumar
Acid, Citrate, Tartrate, Succinate, Glue
It is a connate salt. Mesylate salts are preferred. Must
If necessary, the compound of the formula as the free base is
The acid addition salt is reacted with a suitable acid to form a suitable
It can be obtained by extraction with a suitable organic solvent. Compounds of the formula and acidification thereof suitable as pharmaceuticals
Salt has activity as an antidepressant and antifatigue agent.
and has value in the treatment of depression and fatigue.
The compound can be administered orally and parenterally.
Depending on the route, it can be administered to patients in need of treatment.
Ru. Oral administration of the compounds is preferred. in general
are these compounds available to patients in need of treatment?
Approximately 0.1 to 100 mg/Kg body weight orally at least once a day
Administer. Approximately 0.5-10 mg/Kg/day is preferred.
If parenteral or intravenous administration is required, these drugs
1 kg of the patient requiring treatment
Approximately 0.1 to 10 mg can be administered per day. However, the cure
Symptoms of patient requiring treatment, specific compound used
Variations in dosage may be required depending on the The compound may be present alone or in a pharmaceutically suitable carrier.
Or in combination with a diluent, once or in several doses.
Can be administered. Suitable drug carriers include inert diluents or
are fillers, sterile aqueous solutions and various organic solvents.
Ru. A novel compound of formula or a salt thereof and pharmaceutically suitable
Pharmaceutical composition tablets prepared by mixing with a suitable carrier,
Various powders, capsules, lozenges, syrups, etc.
can be easily administered in the form of If necessary, these
Pharmaceutical compositions include ingredients such as flavoring agents, binders, excipients, etc.
can be added. For oral administration, sodium citrate
Tablets containing various excipients such as thorium are
silica, alginic acid, and certain composite silicas.
various disintegrants, polyvinyl-pyrrolidone,
Binders such as sucrose, gelatin and gum arabic
They can be used together. Compounds of the invention as antidepressant, antifatigue agents
Activity is determined by various pharmacological tests. for example,
“Learned Helplessness”
Porsolt's School of Helplessness
Leaning model, i.e. forced switch of rats.
Immobility induced by ming [R.D.Porsolt
et al., Europlan J.Pharmacol.47, 379 (1978)]
Determined by. This species has therapeutic effects on humans.
In this model, the drug is
known to reduce induced immobility.
Ru. The invention is illustrated in the following examples, which are described herein.
UNDERSTAND THAT YOU ARE NOT LIMITED TO THE DETAILS SET FORTH
I want to be All temperatures are Mr. Setsu. Manufacturing example A 4-chloro-7-fluoro[1,2,4]tri
Azolo[4,3-a]quinoxaline a 2-chloro-6-fluoro-3-methoxy
Manufacture of noxaline 52g (0.24mol) in a flame-dried reaction flask.
2,3-dichloro-6-fluoroquinoxa
Add phosphorus and 500ml of methanol to the slurry.
6.6g dissolved in 650ml methanol under nitrogen gas
(0.29 mol) of sodium metal is boiled at 50℃.
Create and add. The reaction mixture was heated at 50°C overnight;
(i.e. for about 16 hours) the resulting clear solution at room temperature.
Cool to (~20°C). Concentrate the reaction mixture under vacuum
Dissolve the residue in chloroform, wash with water, and remove
Dry with magnesium hydrosulfate. Pass the desiccant
and evaporate under reduced pressure. The obtained liquid residue
Use 1000ml of silica gel and drain with toluene.
and perform chromatography. only the product
The containing fractions were combined to yield 48.3 g (95%) of pure 2-chlorine.
lo-6-fluoro-3-methoxyquinoxaline
obtain. m.p.93−95℃. Mass spectrum m/e212
(p); m/e214 (p+2). b 6-fluoro-2-hydrazino-3-methoxy
Manufacture of siquinoxaline 47 g (0.22 mol) of 2-chloro-6-fluoro
-3-methoxyquinoxaline in 1000ml of ethanol
27.6 g (0.55 mol) of hydra in a solution of
Add gin hydrate (26.8ml). chamber the mixture
Stir overnight at room temperature (ie, about 16 hours at about 20°C).
Add another 9.0 ml of hydrazine hydrate and mix the reaction.
The mixture is stirred at room temperature for 4 hours. At this point, the precipitation
Filtered and washed with ethanol, 43.3g (94%) of pure 6
-Fluoro-2-hydrazino-3-methoxyquino
Get Xarin. m.p.170−174℃ (decomposed). c 7-fluoro-4-methoxy[1,2,4]
Production of triazolo[4,3-a]quinoxaline 15 g (0.072 mol) of 6-fluoro-2-hydro
Radino-3-methoxyquinoxaline and 250ml
While stirring the mixture of triethyl orthoformate,
Stir overnight (~16 hours) at 100°C in an oil bath.
Cool the mixture to room temperature and filter the resulting precipitate under reduced pressure.
Take it. This was washed with ethanol and 11.3g (72g) was washed with ethanol.
%) of pure 7-fluoro-4-methoxy [1,2,
4] Triazolo[4,3-a]-quinoxaline
obtain. m.p.245−246℃ (decomposition). d 7-fluoro-4-hydroxy [1,2,
4] Triazolo[4,3-a]quinoxaline
manufacturing 11.3 g (0.52 mol) of 7-fluoro-4-meth
Ki[1,2,4]triazolo[4,3-a]ki
Noxaline, 115ml 1NHydrochloric acid and 345ml glacial acetic acid
Stir the mixture for 3 hours. After this, the reaction mixture
Cool at room temperature and pour into ice water. mixture
Stir for 30 minutes and filter to remove the precipitate. Wash with water and air dry
8.9 g (84%) of pure 7-fluoro-4-hydro
Ki[1,2,4]triazolo[4,3-a]ki
Get Noxaline. m.p.＞300℃, mass spectrum
Le: m/e, 204 (p). e 4-chloro-7-fluoro[1,2,4]t
Riazolo[4,3-a]quinoxaline Under dry nitrogen gas in a flame-dried reaction flask.
8.9 g (0.044 mol) of 7-fluoro-4-hydro
Ki[1,2,4]triazolo[4,3-a]ki
Noxaline & 160ml phosphorus oxychloride, 8.9ml
Add tri-n-propylamine. reaction mixture
Reduce overnight for about 16 hours. cooled to room temperature
Then, pour into ice water while stirring. Bring the mixture to room temperature
After stirring for 30 minutes at
Wash. Grind this with ethyl acetate, 7.0g
(71%) of 4-chloro-7-fluoro[1,2,
4] Obtain triazolo[4,3-a]quinoxaline
Ru. m.p.305−308℃. Mass spectrum: m/e222
(P); m/e224 (P+2) Manufacturing example B 4-chloro-1-ethyl-7-fluoro[1,
2,4] triazolo[4,3-a] quinox
hmm a 1-ethyl-7-fluoro-4-methoxy
[1,2,4]triazolo[4,3-a]quino
Manufacture of xaline 15 g (0.07 mol) of 6-fluoro-2-hydra
Dino-3-methoxyquinoxaline (Production Example A(b))
product) and 250 ml of triethyl orthopropyl
onate mixture at 100 °C in an oil bath under stirring.
Heat overnight (about 16 hours). Cool the mixture to room temperature.
Cool (~20℃). Wash the precipitate with ethanol.
11.3 g (64%) of pure 1-ethyl-7-fur
Oro-4-methoxy[1,2,4]triazolo
[4,3-a] Quinoxaline is obtained. m.p.200−
202℃ (decomposition). b 1-ethyl-7-fluoro-4-hydroxy
[1,2,4]triazolo[4,3-a]quino
Manufacture of xaline 11.3 g (0.046 mol) of 1-ethyl-7-fur
Oro-4-methoxy[1,2,4]triazolo
[4,3-a] Quinoxaline, 115ml 1Nhydrochloric acid,
The mixture of 345 ml of glacial acetic acid is refluxed for 3 hours. this
After that, the reaction mixture was cooled to room temperature and poured into ice water.
Ru. The mixture was then stirred for 30 minutes and filtered to remove the solids.
take. After washing with water and air drying, 6.6g (62%) of pure 1-
Ethyl-7-fluoro-4-hydroxy [1,
2,4]triazolo[4,3-a]quinoxaline
get. m.p.＞300℃, mass spectrum: m/
e232 (P); m/e231 (P-1). c 4-chloro-1-ethyl-7-fluoro
[1,2,4]triazolo[4,3-a]quino
Manufacture of xaline 6.6 g (0.028 mole) in a flame-dried reaction flask
1-ethyl-7-fluoro-4-hydroxy
C[1,2,4]triazolo[4,3-a]quino
Xaline and 120ml phosphorus oxychloride, 6.6ml
Add li-n-propylamine. 1 of the mixture
In the evening, reflux for about 16 hours. After cooling to room temperature, stir
Pour into ice water. solid product obtained by
Wash the material with cold water and dissolve in ethyl acetate. Next
Water and saturated sodium bicarbonate were added in sequence to the organic solvent solution.
Wash with water and saturated saline. Magnesium sulfate anhydride
Dry in a humidifier and filter to remove the desiccant. Reduce solvent
Evaporation under pressure gives a brown solid. This is diethyl ether
4 g (57%) of pure 4-chloro-1
-ethyl-7-fluoro[1,2,4]triazo
B[4,3-a]quinoxaline is obtained. m.
p.203−205℃. Mass spectrum: m/e250 (P),
m/e252 (P+2), m/e249 (P-1). Manufacturing example C 4,7-dichloro[1,2,4]triazolo
[4,3-a] Quinoxaline a 2,3-dihydroxy-6-chloroquinoxa
production of phosphorus 100 g (0.07 mol) of 4-chloro-1,2-ph
Enylenediamine and 750ml diethyloxale
Reflux the mixture overnight for about 16 hours. this
Afterwards, the reaction mixture is cooled to room temperature (~20 h) and filtered.
Ru. The obtained product was washed with ethanol and air-dried.
140 g of pure 2,3-dihydroxy-6-chloro
Get Quinoxaline. m.p.＞260. b Production of 2,3,6-trichloroquinoxaline 140 g (0.70 mol) of 2,3-dihydroxy-
6-chloroquinoxaline and 326 ml (3.50 moles)
of phosphorus oxychloride overnight (1-16 hours)
After refluxing, pour on ice. Strain the mixture
After washing the product with water and air drying, dissolve it in chloroform.
vinegar. Wash the solution with saturated saline and soak in anhydrous sulfuric acid
Dry with cium. Remove the desiccant through filtration and reduce the pressure.
To leave. Viscous slurry in chloroform/ethano
120g (74%) of pure 2,3,6
- Obtain trichloroquinoxaline. m.p.139−142
℃. Mass spectrum: m/e232 (P), m/e234
(P+2), m/e236 (P+4). c) 2,3-dichloro-3-methoxyquinoxa
production of phosphorus 11.7 g (0.05 mol) of 2,3,6-trichloro
Slurry of quinoxaline in 140ml methanol
- was heated to 50℃ and dissolved in 140ml of methanol.
A solution of 1.4 g (0.06 mol) of sodium metal in 6
Drip over time. The mixture was incubated at 50 °C overnight (~16
time) and then dissolved in 20ml of methanol.
A solution of 140 mg of sodium is added over 1 hour.
The final reaction mixture was heated at 50 °C for 2 h and cooled to room temperature.
reject This mixture was distilled off under vacuum and chloroform was removed.
Mu/dissolve in water. Separate the organic phase and chlorinate the aqueous phase.
Extract with loform. organic phase (i.e. chlorophosate)
lum) and washed sequentially with water and saturated saline.
and dry with anhydrous magnesium sulfate. past
The drying agent is removed and the solvent is distilled off under reduced pressure. leftovers
Distilled with toluene using a 250ml silica gel column.
and perform chromatography. contains products
The fractions were combined to yield 9.8 g (86%) of pure 2,6-dichloride.
Rolo-3-methoxyquinoxaline as a white solid
and get it. m.p.9.2−95℃. d 6-chloro-2-hydrazino-3-methoxy
Production of quinoxaline 4.9 g (0.02 mol) of 2,6-dichloro-3-
Methoxyquinoxaline, 2.7g, (0.053mol)
Hydrazine hydrate (2.6ml), 75ml ethanol
overnight at room temperature (i.e. at about 20°C).
16 hours) Stir. After this, the mixture is filtered and allowed to settle.
Wash the lees with ethanol to obtain 4.4g (98%) of pure 6-
Chloro-2-hydrazino-3-methoxyquinoxa
Get phosphorus. m.p.175−179℃ (decomposed). Masupe
ctor: m/e224 (P); m/e226 (P+2). e 7-chloro-4-methoxy[1,2,4]to
Production of riazolo[4,3-a]quinoxaline 1.4 g (0.0062 mol) of 6-chloro-2-hydride
Radino-3-methoxyquinoxaline, 20ml tri
The mixture of ethyl orthoformate is stirred in an oil bath.
Heat at medium 100°C overnight (~16 hours). chamber the mixture
Cool to a warm temperature and filter the formed precipitate to remove ethanol.
Wash with water. 1.0g (69%) of 7-chloro-4
-methoxy[1,2,4]triazolo[4,3-
a] Obtain quinoxaline. m.p.250−252℃. f 7-chloro-4-hydroxy [1,2,4]
Production of triazolo[4,3-a]quinoxaline 3.4 g (0.014 mol) of 7-chloro-4-methoxy
C[1,2,4]triazolo[4,3-a]quino
Xaline, 35ml 1Nof hydrochloric acid and 105ml of glacial acetic acid
The mixture is refluxed for 2.5 hours. After this, the reaction mixture
Cool to room temperature and pour into ice water. mixture
Stir for 20 minutes. A solid product is obtained by filtration. water this
Washed and air dried 2.6g (87%) pure 7-chloro-4-
Hydroxy[1,2,4]triazolo[4,3-
a] Obtain quinoxaline. m.p.＞300℃. g 4,7-dichloro[1,2,4]triazolo
[4,3-a] Production of quinoxaline in a flame-dried reaction flask under nitrogen gas,
2.6 g (0.012 mol) of 7-chloro-4-hydroxy
C[1,2,4]triazolo[4,3-a]quino
Xaline 40ml phosphorus oxychloride, 2.6ml tri-
Add n-propylamine. Next, add 1 reactant
In the evening, reflux for about 16 hours. Cool to room temperature and serve
Pour the chestnuts into ice water. Ethyl acetate mixture
The extract was extracted with water and saturated hydrogen carbonate solution in order.
Wash sequentially with thorium and saturated saline. anhydrous sulfur
After drying with magnesium chloride, remove the desiccant by filtration.
Evaporation under reduced pressure yields a yellow solid product. this
Using a 200ml silica gel column, chloroform
Elute and chromatize with methanol/methanol (9:1 vol).
Perform tographies. Combine the desired fractions,
Distilled under vacuum to give pure 4,7-dichloro as an orange solid.
[1,2,4] triazolo [4,3-a] mushroom
Obtain 1.89g (66%) of sarin. m.p.253−256℃
(Disassembly). Mass spectrum: m/e238(P), m/
e240 (P+2), m/e242 (P+4) Manufacturing example D 4,7-dichloro-1-ethyl [1,2,4]
Triazolo[4,3-a]quinoxaline a 7-chloro-1-ethyl-4-methoxy
[1,2,4]triazolo[4,3-a]quino
Manufacture of xaline 5.1 g (0.022 mol) of 6-chloro-2-hydra
Dino-3-methoxyquinoxaline (Production Example C(d))
product), 60 ml of triethyl orthopropione
The mixture was stirred in an oil bath at 100°C overnight (~
16 hours). Cool the mixture to room temperature (~20
℃), and remove the precipitate by filtration under reduced pressure. diethyl
Wash with ether to obtain 4.3 g (75%) of pure 7-chlorine.
rho-1-ethyl-4-methoxy[1,2,4]to
Riazolo[4,3-a]quinoxaline is obtained.
m.p.221−223℃. b 7-chloro-1-ethyl-4-hydroxy
[1,2,4]triazolo[4,3-a]quino
Manufacture of xaline 4.3 g (0.0072 mol) of 7-chloro-1-ethyl
Ru-4-methoxy[1,2,4]triazolo
[4,3-a] Quinoxaline, 40ml 1Nhydrochloric acid,
Reflux the mixture in 60 ml of methanol overnight. room temperature
The precipitate formed is collected by filtration and methane
Wash with a towel. Thus 3.7g (94%) of pure 7
-chloro-1-ethyl-4-hydroxy [1,
2,4]triazolo[4,3-a]quinoxaline
get. m.p.＞300℃. c 4,7-dichloro-1-ethyl [1,2,
4] Triazolo[4,3-a]quinoxaline
manufacturing under nitrogen gas in a flame-dried reaction flask.
5.1 g (0.02 mol) of 7-chloro-1-ethyl-
4-hydroxy[1,2,4]triazolo[4,
3-a] Quinoxaline 75ml phosphorus oxychloride, 5
ml of tri-n-propylamine. reaction mixture
The mixture is refluxed overnight for about 16 hours. Cool to room temperature and boil
Make and pour into ice water. 15 minutes of mixture at room temperature
Stir for a minute. filtrate and wash the resulting solid with cold water.
4.2 g (79%) of pure 4,7-dichloro-1
-ethyl[1,2,4]triazolo[4,3-
a] Obtain quinoxaline. m.p.217−220℃ (min
solution). Mass spectrum: m/e226 (P), m/e268
(P+2), m/e265 (P-1). Manufacturing example E 4-chloro-7-methoxy[1,2,4]tri
Azolo[4,3-a]quinoxaline a 2,3-dihydroxy-6-methoxykinoki
sarin manufacturing 20 g (0.114 mol) of 4-methoxy-o-Hue
Nylene diamine, 11 g (0.114 mol) triethylene
Dissolve Ruamine in 200ml of diethyl oxalate.
The mixture was refluxed overnight for about 16 hours. After this,
The reaction mixture was cooled to room temperature (~20 °C) and filtered.
Get the product. Wash with ethanol and remove 14.8g (68
%) of pure 2,3-dihydroxy-6-methoxy
Noxaline (m.p.>300°C) is obtained. mass spec
Tor: m/e192 (P). b 2,3-dichloro-6-methoxyquinoxane
manufacturing Dry nitrogen gas into the flame-dried reaction flask.
Bottom, 14.8 g (0.77 mol) of 2,3-dihydroxy
-6-Methoxyquinoxaline, 75 ml oxychloride
phosphorus, add 15 ml of tri-n-propylamine.
Ru. Stir the exothermic reaction mixture at room temperature (20°C) for 1 hour.
Then reflux overnight (~16 hours). After this the mixture
Cool to room temperature. Pour the mixture into ice water.
Stir for 20 minutes at room temperature. Remove the precipitate through filtration and wash with water.
and dissolve in chloroform. Insoluble matter through solution
Add water and saturated sodium bicarbonate to the solution in order.
Wash with water and saturated saline. Washed solution
Concentrate under vacuum and recrystallize the residue with ethanol.
14.2 g (80%) of pure 2,3-dichloro-6-methane
Obtain Toxyquinoxaline. m.p.156−159℃, m.p.
Spectrum: m/e228 (P), m/e230 (P+
2), m/e232 (P+4) c 2-chloro-3,6-dimethoxyquinoxane
manufacturing Dry nitrogen gas into the flame-dried reaction flask.
Below, 7.1g of 2, added to 60ml of methanol.
3-dichloro-6-methoxyquinoxaline slurry
850 mg of metal dissolved in 80 ml of methanol
Slowly prepare a solution of sodium at 50℃ for 7 hours.
drip. Heat the mixture at 50°C overnight and cool to room temperature.
reject After this, the mixture is concentrated under vacuum to remove the residue.
Dissolve in loloform. Anhydrous magnesium sulfate after washing with water
Dry in a vacuum. to remove desiccant and reduce solvent.
Distill under pressure. Remove the residue with 400ml of silica gel.
Elution with toluene and chromatography
When the fractions containing the target product are combined and distilled under vacuum,
6.1 g (88%) of pure, 2-chloro-3,6-dimethane
A white solid of Toxyquinoxaline is obtained. m.p.79
−81℃. Elemental preference: C_TenH₉ClN₂O₂as Calculated value: C, 53.47; H, 4.04; N, 12.47 Actual value: C, 53.29; H, 4.05; N, 12.28 d 3,6-dimethoxy-2-hydrazinokinoki
sarin manufacturing 5 g (0.022 mol) of 2-chloro-3,6-di
Methoxyquinoxaline, 2.8 g (0.056 mole)
Drazine hydrate (2.7ml), 75ml ethanol
Heat the mixture to 50°C overnight. After this, further
Add 1.0ml hydrazine hydrate into the mixture;
Heat at 50°C for 6 hours. Additionally 1.0ml hydrazine
Add hydrate and heat to 50°C overnight. this
Cool to room temperature and filter the mixture. Remove the precipitate
4.1 g (85%) of pure, 3,6-di
Methoxy-2-hydrazinoquinoxaline is obtained.
m.p.128−130℃ (decomposition). e 4,7-dimethoxy[1,2,4]triazo
B [4,3-a] Production of quinoxaline 1.5 g (0.068 mol) of 3,6-dimethoxy-2
- hydrazinoquinoxaline, 20 ml triethyl
The lutformate mixture was stirred in an oil bath at 100%
Heat overnight (~16 hours) at °C. Bring mixture to room temperature
Cool, filter the formed precipitate, and remove with ethanol.
Upon washing, 1.8 g of pure, 4,7-dimethoxy
[1,2,4] triazolo [4,3-a] mushroom
Get sarin. m.p.238−240℃ (decomposition). Masus
Spectrum: m/e230 (P), m/e231 (P+1),
m/e232 (P+1) f 4-hydroxy-7-methoxy [1,2,
4] Triazolo[4,3-a]quinoxaline
manufacturing 1.6g (0.0069mol) of 4,7-dimethoxy
[1,2,4] triazolo [4,3-a] mushroom
Sarin, 16ml 1NA mixture of hydrochloric acid, 48ml glacial acetic acid
Reflux for 3 hours. After this, pour the mixture onto ice
Open, pass. Take the product on the funnel and
When washed with chill ether, 1.19g (80%) of
Pure, 4-hydroxy-7-methoxy [1,2,
4] Obtain triazolo[4,3-a]quinoxaline
Ru. m.p.＞250℃. g 4-chloro-7-methoxy[1,2,4]to
Production of riazolo[4,3-a]quinoxaline in a flame-dried flask under dry nitrogen gas,
1.1 g (0.0055 mol) of 4-hydroxy-7-methane
Toxi[1,2,4]triazolo[4,3-a]
Quinoxaline, 15ml Phosphorous Oxychloride, 1.0ml
Add tri-n-propylamine. 1 of the mixture
In the evening, reflux for about 16 hours, cool to room temperature, and slowly cool.
Pour into ice water. Extract the mixture with ethyl acetate
Then wash the extract sequentially with water and saturated saline.
Ru. Dry with anhydrous magnesium sulfate and filtrate to dryness.
After removing the agent, the solvent is distilled off by concentration under reduced pressure. Leftovers
of chloroform using a 150 ml silica gel column.
Drain with methanol/methanol (95:5 volume) and cool.
Perform romatography. Combine the fractions containing the target product.
Then, concentrate under vacuum. Dissolve the residue in chloroform/di
Recrystallized with ethyl ether, 400 mg (31%) pure,
4-chloro-7-methoxy[1,2,4]thoria
Zolo[4,3-a]quinoxaline is obtained. m.
p.266−268℃ (decomposition). Mass spectrum: m/
e234 (P), m/e236 (P+2). Manufacturing example F 4-chloro-1-ethyl-7-methoxy [1,
2,4] triazolo[4,3-a] quinox
hmm a 1-ethyl-4,7-dimethoxy[1,2,4]
Production of triazolo[4,3-a]quinoxaline 4.0 g (0.018 mol) of 3,6-dimethoxy-2
-Hydrazinoquinoxaline (Production of Preparation Example E(d))
), 50 ml of triethyl orthopropionate
The mixture was kept under stirring in an oil bath at 100 °C overnight (~16
time) heat. Cool the mixture to room temperature (~20 °C)
Then, remove the precipitate by suction. ethanol
3.3 g (72%) of pure, 4,7-dimethane
xy-1-ethyl[1,2,4]triazolo
[4,3-a] Quinoxaline is obtained. m.p.184−
188℃. Mass spectrum: m/e258(P), m/
e228 (P-30). b 1-ethyl-4-hydroxy-7-methoxy
[1,2,4]triazolo[4,3-a]quino
Manufacture of xaline 3.3 g (0.013 mol) of 4,7-dimethoxy-1
-ethyl[1,2,4]triazolo[4,3-
a] Quinoxaline, 3.3ml 1NHydrochloric acid, 99ml
The glacial acetic acid mixture is refluxed for 2 hours. After this, mix
Cool things to room temperature and pour into ice water. reaction mixture
The mixture was stirred at room temperature for 20 minutes and then extracted with ethyl acetate.
Ru. After washing the extract with saturated saline, place it in an anhydrous sulfuric acid mug.
Dry with nesium. Remove the desiccant by
The solvent is distilled off under reduced pressure. Wash the yellow solid with water and air dry.
1.87g (67%) of 1-ethyl-4-hydroxy
-7-methoxy[1,2,4]triazolo[4,
3-a] Obtain quinoxaline. m.p.＞250℃. c 4-chloro-1-ethyl-7-methoxy
[1,2,4]triazolo[4,3-a]quino
Manufacture of xaline Under dry nitrogen gas into a flame-dried reaction flask.
1.87 g (0.0076 mol) of 1-ethyl-4-hydro
xy-7-methoxy[1,2,4]triazolo
[4,3-a]quinoxaline, 25 ml oxychloride
phosphorus, add 1.8 ml of tri-n-propylamine.
Ru. The mixture is refluxed overnight for about 16 hours. up to room temperature
After cooling, pour slowly into ice water. blend
The solid product obtained by stirring at room temperature for 30 minutes was cooled.
Wash with water. Dissolve this in chloroform and saturate
After washing with saline, dry with anhydrous magnesium sulfate.
dry Remove the desiccant and remove the solvent under reduced pressure.
A yellow solid is then obtained. diethyl ether
Grind and strain to obtain 1.6 g (80%) of pure, 4-
Chloro-1-ethyl-7-methoxy [1,2,
4] Obtain triazolo[4,3-a]quinoxaline
Ru. m.p.173−175℃. Mass spectrum: m/e,
262(P); m/e, 264(P+2); m/e261(P-
1) Manufacturing example G 4-chloro-8-fluoro[1,2,4]tri
Azolo[4,3-a]quinoxaline a 2,3-dihydroxy-6-fluorokinoki
sarin manufacturing 26.3 g (0.19 mol) of 4-fluoro-1,2-
Phenylenediamine [Journal of the American
Chemical Society, Vol75, p1294 (1953)], 150
ml diethyl oxalate, a mixture of nitrogen gas
Reflux for under 18 hours. Bring the reaction mixture to room temperature (~20 °C)
Cool and pass. Pour the obtained product into 100 ml of evaporator.
After washing 4 times with tanol and air drying, 19.3g (80%)
Pure, 2,3-dihydroxy-6-fluorokinoki
Get sarin. m.p.＞300℃, (literature value m.p.387−
390℃, US Patent No. 3992378) Mass Spect
Le: m/e, 180(P) b 2,3-dichloro-6-fluoroquinoxalin
manufacturing 19 g (0.105 mol) of 2,3-dihydroxy-
6-fluoroquinoxaline, 50 ml oxychloride
Reflux overnight (~16 hours). Cool to room temperature;
Stir well and pour over 200g of ice. blend
28.2g of 2,3-dichloro
-6-fluoroquinoxaline is obtained. m.p.148−
152℃. c 2-chloro-6-fluoro-3-hydrazino
Production of quinoxaline 28.2g (0.105 mole) in 500ml ethanol
2,3-dichloro-6-fluoroquinoxaline
15 ml (0.31 mol) of hydrazine hydrate in a suspension of
Add the salt over 2 minutes and a dark red suspension will form.
can get. The mixture was stirred and stirred at room temperature for 20 hours.
Ru. Filter the formed precipitate and wash it several times with ethanol.
do. Air-dried, 20.7 g (93%) pure 2-chloro-
Obtained 6-fluoro-3-hydrazinoquinoxaline
Ru. m.p.190−192℃ (decomposition). d 4-chloro-8-fluoro[1,2,4]t
Production of riazolo[4,3-a]quinoxaline 10 g (0.047 mol) of 2-chloro-6-fluoro
Rho-3-hydrazinoquinoxaline, 80ml (0.47mol)
) Triethyl orthoformate in nitrogen gas
Heat in an oil bath overnight (~16 hours) with stirring.
do. Cool the mixture to room temperature and aspirate the precipitate.
pass Wash 3 times with 50 ml of ethanol and air dry.
9.42 g (91%) of pure 4-chloro-8-fluoro
[1,2,4] triazolo [4,3-a] mushroom
Get sarin. m.p.310−312℃ (decomposed). Masus
Spectrum: m/e224, 223, 222 (P+). Manufacturing example H 4-chloro-1-ethyl-8-fluoro[1,
2,4] triazolo[4,3-a] quinox
hmm 10.0g (0.047mol) of 2-chloro-6-fur
Oro-3-hydrazinoquinoxaline (Production Example G(c)
product), 95 ml (0.47 mol) of triethylol
Stir the topropionate mixture under nitrogen gas.
while heating at 100°C in an oil bath overnight (~16 hours).
heat. The mixture was cooled to room temperature (~20 °C).
Aspirate the precipitate. It with 50ml ethanol
Each was washed three times and air dried to give 7.5g (65%) of pure 4.
-chloro-1-ethyl-8-fluoro[1,2,
4] Obtain triazolo[4,3-a]quinoxaline
Ru. m.p.160−163℃ (decomposition). Mass spectrum:
m/e, 249, 250, 251, 252 (P+). Manufacturing example I 4-chloro-8-fluoro-1-trifluoro
Methyl[1,2,4]triazolo[4,3-
a] Quinoxaline a 8-fluoro-4-hydroxy-1-trif
fluoromethyl[1,2,4]triazolo[4,
3-a] Production of quinoxaline 12.8 g (0.06 mol) of 2-chloro-6-fluoro
Rho-3-hydrazinoquinoxaline, 50 ml (0.65 molar
Dry the trifluoroacetic acid mixture with nitrogen gas
Heat to 120℃ for 24 hours while stirring to make a homogeneous solution.
get. Pour the mixture into ice water while stirring and
Stir and strain for 30 minutes. Wash the product 3 times with water
and dry under vacuum at 80°C. 12.58g (77%)
Pure, 8-fluoro-4-hydroxy-1-trif
fluoromethyl[1,2,4]triazolo[4,3
-a] Obtain quinoxaline. m.p.298−302℃. Ma
Spectrum: m/e, 272 (P+) b 4-chloro-8-fluoro-1-trifluoro
lomethyl[1,2,4]triazolo[4,3-
a] Production of quinoxaline Dry in a flame-dried 250 ml three-necked reaction flask.
Introducing dry nitrogen gas, 12.5 g (0.046 mol) of 8
-Fluoro-4-hydroxy-1-trifluoro
Methyl[1,2,4]triazolo[4,3-a]
Quinoxaline, 85ml Phosphorous Oxychloride, 17.5ml
Add tri-n-propylamine. 1 of the mixture
In the evening, reflux for about 16 hours and cool to room temperature. stirring
Slowly pour into 1000ml of ice water. mixture
Stir the mixture for an additional 30 minutes at room temperature. 300ml Chloropho
extract with rum, in turn, saturated sodium bicarbonate
Wash with water, water, and saturated saline. Anhydrous sulfate magne
Remove the desiccant by drying with sodium chloride. Decompression
The lower solvent was distilled off and 10.47g (79%) of pure 4-chloro
rho-8-fluoro-1-trifluoromethyl
[1,2,4] triazolo [4,3-a] mushroom
Sarin is obtained as a yellow solid. m.p.135−138
°C, mass spectrum: m/e292/290 (P+) Manufacturing example J 4-chloro-7,8-difluoro[1,2,
4] Triazolo[4,3-a]quinoxaline a 2,3-dihydroxy-6,7-difluoro
Production of quinoxaline 11.3 g (0.0784 mol) of 4,5-difluoro-
o-Phenylenediamine (U.S. Patent, no.
4264600) and 80 ml (0.589 mol) of diethyl oxalate was refluxed for 4 hours to obtain a precipitate. The reaction mixture is cooled to room temperature (~20°C) overnight. The solid obtained by filtration was washed several times with diethyl ether and air-dried to give 15.5 g of pure, 2,3
-Dihydroxy-6,7-difluoroquinoxaline is obtained. mp>310℃, mass spectrum: m/
e198(P+) b Manufacture of 2,3-dichloro-6,7-difluoroquinoxaline 15.4 g (0.078 mol) of 2,3-dihydroxy-6,7-difluoroquinoxaline, 39 g
A mixture of (0.187 mol) phosphorus pentachloride and 20 ml (0.22 mol) phosphorus oxychloride is refluxed under stirring for 4 hours. While the reaction continues, add another 20 ml of phosphorus oxychloride under stirring (the reaction mixture becomes a homogeneous solution within 30 minutes). The reaction mixture was stirred overnight (~16 hours) at room temperature to give a flame-yellow precipitate. Pour the mixture into 200 g of ice water and stir while cooling to obtain a brown solid, 2.
20.9 g of 3-dichloro-6,7-difluoroquinoxaline is obtained. mp162−164℃ (decomposed). Mass spectrum: m/e, 238/236/234 (P+). c Preparation of 2-chloro-6,7-difluoro-3-hydrazinoquinoxaline 10 g (0.0426 mol) of 2,3-dichloro-6,
7-difluoroquinoxaline, 5 ml (0.03 mol)
of hydrazine hydrate, 200ml of ethanol,
The mixture is stirred at room temperature for 24 hours to obtain a faded red precipitate. This slurry was filtered, washed twice with 20 ml of ethanol, and air-dried to yield 5.99 g (67
%) pure, 2-chloro-6,7-difluoro-3
- Obtaining hydrazinoquinoxaline. mp212−215
°C (decomposition), mass spectrum, m/e, 230 (P);
m/e, 232 (P+2) d 4-chloro-7,8-difluoro[1,2,
4] Production of triazolo[4,3-a]quinoxaline 5.99 g (0.026 mol) of 2-chloro-6,7-
Difluoro-3-hydrazinoquinoxaline, 30ml
(0.18 mol) of triethyl orthoformate is heated at 100° C. for 24 hours to obtain a reddish-brown solid.
The slurry was cooled to room temperature and the filtered product was washed with diethyl ether, yielding 5.15 g (82%).
Pure, 4-chloro-7,8-difluoro[1,
2,4]triazolo[4,3-a]quinoxaline is obtained. mp＞210℃(decomposition). Mass spectrum:
m/e, 242/240 (P+). Production example K 4-chloro-6,7-difluoro-1-ethyl[1,2,4]triazolo[4,3-a]quinoxaline 7.0 g (0.03 mol) of 2-chloro-6,7-difluoro-3 - A mixture of hydrazinoquinoxaline (product of Preparation J(c)), 60 ml (0.30 mol) of triethylorthopropionate is heated in an oil bath with stirring under nitrogen gas at 100° C. for 24 hours. The mixture is cooled to room temperature (~20°C) and the red precipitate that forms is filtered off with suction and washed twice with diethyl ether.
Air-dried 4.15 g (52%) pure, 4-chloro-6,7
-difluoro-1-ethyl[1,2,4]triazolo[4,3-a]quinoxaline is obtained. m.
p.185-186℃ (decomposition). Production example L 4,8-dichloro-1-methyl [1,2,4]
Triazolo[4,3-a]quinoxaline a Preparation of 2,6-dichloro-6-hydrazinoquinoxaline 23 g (0.10 mol) 2,3,6-trichloroquinoxaline, 11 g (0.22 mol) hydrazine hydrate, 500 ml Bring the ethanol mixture to room temperature (~
Stir overnight (~16 hours) at 20°C. Filter the formed precipitate and wash it with ethanol to give 22.2g.
(97%) pure 2,6-dichloro-3-hydrazinoquinoxaline is obtained. mp>250°C, mass spectrum: m/e, 228(P). b 4,8-dichloro-1-methyl [1,2,
4] Production of triazolo[4,3-a]quinoxaline 20 g (0.087 mol) of 2,6-dichloro-3-
A mixture of hydrazinoquinoxaline and 160 ml (0.87 mol) of triethyl orthoacetate is heated at 100° C. for 20 hours in an oil bath with stirring under nitrogen gas, resulting in a yellow suspension. The mixture is cooled to room temperature and filtered to obtain a solid. Washing with ethanol and air drying yields 10.2 g (46%) of pure 4,8-dichloro-1-methyl[1,2,4]triazolo[4,3-a]quinoxaline. mp＞280
°C, mass spectrum: m/e254/252 (P+). Production example M 4,8-dichloro-1-trifluoromethyl[1,2,4]triazolo[4,3-a]quinoxaline a 8-chloro-4-hydroxy-1-trifluoromethyl[1,2,4] ] Triazolo [4,3
-a] Production of quinoxaline A 500 ml three-neck reaction flask dried with flame was equipped with a stirrer, a nitrogen gas introduction tube, and a reflux condenser.
Add ml (0.87 mol) of trifluoroacetic acid. Stirring was started, and 20 g (0.087 mol) of 2,6-dichloro-3-hydrazinoquinoxaline (Production Example L(a)
product). The mixture is heated in a steam bath for 24 hours and cooled to room temperature. Pour this into 200g of ice water and stir the mixture for 30 minutes. Wash the product obtained through filtration several times with water and air dry (requires about 18 hours).
14.3 g (57%) of pure 8-chloro-4-hydroxy-1-trifluoromethyl[1,2,4]triazolo[4,3-a]quinoxaline are obtained. m.
p.253-255℃ (decomposition), mass spectrum: m/
e290/288 (P+) b Production of 4,8-dichloro-1-trifluoromethyl[1,2,4]triazolo[4,3-a]quinoxaline Add dropwise using a stirrer to a 250 ml three-neck reaction flask dried with flame. A funnel and a reflux condenser were attached, and under nitrogen gas, 14.3 g (0.05 mol) of 8-chloro-4-hydroxy-1-trifluoromethyl [1,2,
4] triazolo[4,3-a]quinoxaline,
Add 100ml of phosphorus oxychloride. This suspension is
19 ml (0.10 mol) of tri-n-propylamine are added dropwise over 5 minutes. The reaction mixture is refluxed for 20 hours resulting in a clear dark red solution. This is cooled to room temperature and poured into 1000 ml of ice water under stirring. The mixture was stirred at room temperature for 30 minutes and then diluted with 500 ml of chloroform.
Extract 3 times each. The extracts are combined and washed sequentially with water, saturated aqueous sodium bicarbonate, water, and saturated brine. Dry over anhydrous magnesium sulfate and filter to remove desiccant. The solvent was removed under reduced pressure to obtain 11.4 g (75%) of pure, yellow 4,8-dichloro-1-trifluoromethyl[1,2,4]triazolo[4,3-a]quinoxaline. m.
p.133-135℃, mass spectrum: m/e308 (P+
2); m/e310 (P+4). Production example N 4,8-dichloro-1-phenyl [1,2,
4] Triazolo[4,3-a]quinoxaline 50.0 g (0.274 mol) of triethyl orthobenzoate is added to a 250 ml three-necked reaction flask equipped with a stirrer and a reflux condenser and heated to about 70°C. Stirring is started and 10.0 g (0.0437 mol) of 2,6-dichloro-3-hydrazinoquinoxaline (product of Preparation L(a)) are added. Mixture about 120
Heat to ℃ and continue stirring for 24 hours. After cooling to room temperature (20° C.), stir overnight (approximately 16 hours) to obtain a yellow slurry. Strain the slurry and remove the solids by 50
ml of ethanol twice and yielded 9.8 g (72%) of crude, 4,8-dichloro-1-phenyl [1,2,
4] Obtain triazolo[4,3-a]quinoxaline. mp305−307℃. Mass spectrum: m/
e316/314 (P+). Example 1 2-chloro-3-hydrazinoquinoxaline 2,3-dichloroquinoxaline (33.5g,
(0.168 mol) is stirred with hydrazine hydrate (18.5 g, 0.369 mol) in 500 ml of ethanol at room temperature overnight (i.e., about 20° C., 16 hours). The deep yellow slurry was filtered, the precipitate was washed with ethanol, and recrystallized with hot methanol, yielding 13.5 g (41
%) of 2-chloro-3-hydrazinoquinoxaline is obtained. mp181℃ (decomposition), mass spectrum:
m/e194(P) Example 2 4-chloro[1,2,4]triazolo[4,3
-a] Quinoxaline 2-chloro-3-hydrazinoquinoxaline (9.0 g, 0.046 mol), (product of Example 1) is stirred with triethyl orthoformate at 100° C. for 1 hour. Cool the mixture to room temperature and filter off the solid precipitate. Washed with cyclohexane and dried 8.8
g (94% yield) of 4-chloro[1,2,4]triazolo[4,3-a]quinoxaline is obtained. m.
p.287−290℃ (decomposition). Mass spectrum: m/
e204(P). Example 3 4-chloro-1-methyl[1,2,4]triazolo[4,3-a]quinoxaline 2-chloro-3-hydrazinoquinoxaline (15.5 g, 0.080 mol), (product of Example 1) ) with triethyl orthoacetate at 100°C for 3 hours. Cool the mixture to room temperature and filter off the solids. Washed with ethanol and air dried to weigh 11.4g.
(65% yield) of 4-chloro-1-methyl [1,2,
4] Obtain triazolo[4,3-a]quinoxaline. mp215-222℃, mass spectrum: m/e218
(P). Example 4 4-chloro-1-ethyl[1,2,4]triazolo[4,3-a]quinoxaline 2-chloro-3-hydrazinoquinoxaline (4.5 g, 0.023 mol) (product of Example 1) with triethyl orthopropionate (50 ml) at 100°C.
Stir for 1 hour. The mixture was cooled to room temperature and filtered to remove the white precipitate. Wash with cyclohexane,
4.5 g (85% yield) of 4-chloro-1-ethyl[1,2,4]triazolo[4,3-a]quinoxaline are obtained. mp158−160℃. Mass spectrum: m/e232 (P). Example 5 4-chloro-1-n-propyl [1,2,4]
Triazolo[4,3-a]quinoxaline 2-chloro-3-hydrazinoquinoxaline (3.0 g, 0.015 mol), (product of Example 1) was dissolved with triethyl orthobutyrate (27 ml) at 100°C.
Stir for an hour. The mixture is cooled to room temperature and the precipitate is filtered off. Wash with cyclohexane and extract the solid with chloroform. Insoluble materials are removed by filtration and the chloroform solution is concentrated under vacuum. Recrystallization from chloroform yields 1.96 g (53% yield) of 4-chloro-1-n-propyl[1,2,4]triazolo[4,3-a]quinoxaline. mp173
−175℃. Mass spectrum: m/e246 (P) Example 6 4-chloro-1-isopropyl [1,2,4]
Triazolo[4,3-a]quinoxaline 2-chloro-3-hydrazinoquinoxaline (4.0 g, 0.02 mol), (product of Example 1) was stirred with triethylorthoisobutyrate (15 ml) at 100°C for 3 hours. do. Cool the solution to room temperature and filter to remove the precipitate. Washed with ethanol and recrystallized with 300 ml of hot ethanol to give 2.06 g (40% yield) of 4
-Chloro-1-isopropyl[1,2,4]triazolo[4,3-a]quinoxaline is obtained. m.
p.208−210℃. Mass spectrum: m/e246 (P). Example 7 4-Methylamino[1,2,4]triazolo[4,3-a]quinoxaline 4-chloro[1,2,4]triazolo[4,3
-a] Quinoxaline (2.0 g, 0.01 mol), (product of Example 2), is dissolved in N,N-dimethylformamide (30 ml), saturated with monomethylamine gas and stirred at room temperature for 3 hours. Further monoethylamine gas is introduced into the solution and stirred for 2 hours at room temperature. The precipitate is removed by filtration and washed with N,N-dimethylformamide. Recrystallization from N,N-dimethylformamide yielded 1.37 g (69% yield) of 4-methylamino[1,2,4]triazolo[4,3-
a] Obtain quinoxaline. mp＞300℃, Mass spectrum: m/e199 (P) Elemental analysis: As C ₁₀ H ₉ H ₅ Calculated value: C, 60.29; H, 4.55; N, 35.15 Actual value: C, 59.99; H, 4.47; N , 35.11 Example 8 4-dimethylamino[1,2,4]triazolo[4,3-a]quinoxaline in N,N-dimethylformamide (30 ml)
2.0g (0.01 mol) of 4-cuchloro[1,2,4]
A slurry of tetrazolo[4,3-a]quinoxaline (product of Example 2) is saturated with dimethylamine gas and stirred overnight at room temperature. Pour the mixture onto ice and filter off the precipitate. Recrystallization from ethanol yields 640 mg (44% yield) of 4-dimethylamino[1,2,4]triazolo[4,3-a]quinoxaline. mp174−186℃. Mass spectrum: m/e, 213 (P) Elemental analysis: As C ₁₁ H ₁₁ N ₅ Calculated value: C, 61.96; H, 5.20; N, 32.84 Actual value: C, 62.26; H, 5.43; N, 32.92 Implemented Example 9 4-ethylamino[1,2,4]triazolo[4,3-a]quinoxaline in N,N-dimethylformamide (30ml)
2.0g (0.01mol) of 4-chloro[1,2,4]
A slurry of triazolo[4,3-a]quinoxaline (product of Example 2) is saturated with monoethylamine gas and stirred at room temperature for 2 hours. Monoethylamine gas is reintroduced to the mixture and stirred for a further 2 hours. The precipitate is removed by filtration and washed with N,N-dimethylformamide. Recrystallize with methanol,
680 mg (32% yield) of 4-ethylamino[1,2,
4] Obtain triazolo[4,3-a]quinoxaline. mp254−6℃. Mass spectrum: m/e,
213(P) Elemental analysis: as C ₁₁ H ₁₁ H ₅ Calculated value: C, 61.96; H, 5.20; N, 32.84 Actual value: 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 mol), (product of Example 2) is stirred with diethylamine (6.5 ml, 0.063 mol) in N,N-dimethylformamide (100 ml) at room temperature for 2 hours. The product precipitates when the reaction mixture is poured into ice water. After this, wash with water. Recrystallize with isopropanol,
3.36 g (66% yield) of 4-diethylamino[1,
2,4]triazolo[4,3-a]quinoxaline is obtained. mp117−119℃. Mass spectrum: m/
e, 241(P). Example 11 4-di-n-propylamino[1,2,4]triazolo[4,3-a]quinoxaline 4-chloro[1,2,4]triazolo[4,3]
-a] Quinoxaline (2.0 g, 0.01 mol) (product of Example 2) and 3.0 g (0.03 mol) di-n
- Propylamine is stirred in N,N-dimethylformamide (50 ml) at room temperature for 3 hours. Pour the solution onto ice and a precipitate will form. Separate by sieving and air dry. Recrystallized from cyclohexane (250 ml) to obtain 1.1 g (41 yield) of 4-di-n-propylamino[1,2,4]triazolo[4,3-a]
Get Quinoxaline. mp240-242°C, mass spectrum: m/e, 269(P). Elemental analysis: C ₁₅ H ₁₉ N ₅ Calculated value: C, 66.89; H, 7.11; N, 26.00 Actual value: C, 66.68; H, 6.97; N, 26.12 Example 12 4-isopropylamino[1,2, 4] Triazolo[4,3-a]quinoxaline 4-chloro[1,2,4]triazolo[4,3
-a] Quinoxaline (2.0 g, 0.01 mol), (product of Example 2) and 1.77 g (0.03 mol) isopropylamine are stirred in N,N-dimethylformamide (30 ml) at room temperature overnight. Pour the dark solution into ice and wash the precipitate with water. Recrystallization from ethanol and then twice from isopropyl ether yielded 1.2 g (53% yield) of 4-isopropylamino[1,2,4]triazolo[4,3-
a] Obtain quinoxaline. mp133-5℃, mass spectrum: m/e, 222 (P) Elemental analysis: as C ₁₂ H ₁₃ N ₅・1/3H ₂ O Calculated value: C, 61.79; H, 5.90; N, 30.02 Actual value: C , 61.51; H, 5.89; N, 29.90 Example 13 4-diethylamino-1-methyl [1,2,
4] Triazolo[4,3-a]quinoxaline Followed the method of Example 11 and used here in place of 4-chloro[1,2,4]triazolo[4,3-a]quinoxaline (product of Example 2) As a starting material, 4-chloro-1-methyl[1,2,4]triazolo[4,3-a]quinoxaline (Example 3
product) and diethylamine instead of di-n-propylamine to produce the title compound. The obtained crude product was recrystallized from chloroform and then from cyclohexane.
7.2 g (54% yield) of pure, 4-diethylamino-
1-methyl[1,2,4]triazolo[4,3-
a] Obtain quinoxaline. m, p.123-5℃. Example 14 4-Amino-1-ethyl[1,2,4]triazolo[4,3-a]quinoxaline 1.2 g (0.005 mol) of 4-chloro-1 dissolved in N,N-dimethylformamide (20 ml) - Ammonia gas is introduced into the solution of ethyl[1,2,4]triazolo[4,3-a]quinoxaline (product of Example 4) at 0° C. for about 2 hours. Solution at 0℃
Stir for 30 minutes, then at room temperature for 1 hour. Pour the mixture into ice and stir for 20 minutes. The precipitate formed is filtered, washed with water, and air-dried. Recrystallized from ethanol to obtain 220 mg (22% yield) of pure 4-amino-1-
Ethyl[1,2,4]triazolo[4,3-a]
Get Quinoxaline. m, p, 284-8℃, mass spectrum: m/e, 213 (P) Elemental analysis: as C ₁₁ H ₁₁ N ₅・1/6H ₂ O Calculated value: C, 61.10; H, 5.28; N, 32.39 Actual value: C, 61.36; H, 5.14; N, 31.96 Example 15 4-methylamino-1-ethyl [1,2,4]
Triazolo[4,3-a]quinoxaline 4-chloro-1-ethyl[1,2,4]triazolo[4,3-a]quinoxaline (1.2 g,
0.005 mol), (product of Example 4), monomethylamine gas is introduced at 00° C. for 2 minutes. After stirring the reaction mixture at 0 °C for 30 min and at room temperature for 2 h,
Pour into ice. Stir for 2 minutes, remove the precipitate that forms and air dry. Recrystallize with ethanol,
1.0 g (88% yield) of 4-methylamino-1-ethyl[1,2,4]triazolo[4,3-a]quinoxaline is obtained. m, p.271-3°C, mass spectrum: m/e, 227 (P). Elemental analysis _value : _C12H13N5・1/ _8H2O Calculated value: C, _62.80 ; H, 5.82; N, 30.51 Actual value: C, 62.72; H, 5.86; N, 30.62 Example 16 4- Dimethylamino-1-ethyl [1,2,
4] Triazolo[4,3-a]quinoxaline 4-chloro-1-ethyl[1,2,4]triazolo[4,3-a]quinoxaline (1.2g, 0.005
mol), (product of Example 4), 676 mg (0.015 mol)
of anhydrous dimethylamine was stirred in N,N-dimethylformamide (50 ml) at 0°C for 30 minutes. The reaction mixture was then stirred at room temperature for 2 hours, poured into ice, and stirred for an additional 20 minutes. The formed precipitate is filtered off, washed with water, and air-dried. Recrystallization from chloroform and then chloroform/cyclohexane yielded 510 mg (42% yield) of 4-dimethylamino-
1-ethyl[1,2,4]-triazolo[4,3
-a] Obtain quinoxaline. m, p, 155-8°C. Mass spectrum: m/e241 (P) Elemental analysis: C ₁₃ H ₁₅ N ₅ Calculated value: C, 64.71; H, 6.27; N, 29.02 Actual value: C, 64.69; H, 6.27; N, 29.32 Example 17 1-ethyl-4-ethylamino [1,2,4]
Triazolo[4,3-a]quinoxaline 4 in N,N-dimethylformamide (50ml)
-Chloro-1-ethyl[1,2,4]triazolo[4,3-a]quinoxaline (1.2 g, 0.005 mol), (product of Example 4) mixed with monoethylamine gas at 0°C for 2 min. Introduce. clear solution to 0
Stir for 30 minutes at °C and then for 2 hours at room temperature.
Pour the reaction mixture into ice and filter off the precipitate. Wash with water and air dry. Recrystallize with ethanol,
1.0 g (83% yield) of pure 1-ethyl-4-ethylamino[1,2,4]triazolo[4,3-
a] Obtain quinoxaline as a white solid. (m,
p.235-238℃). Mass spectrum: m/e, 241
(P) Elemental analysis: C ₁₃ H ₁₅ N ₅ Calculated value: C, 64.71; H, 6.27; N, 29.02 Actual value: C, 64.57; H, 6.20; N, 29.15 Example 18 4-diethylamino-1- Ethyl [1,2,
4] Triazolo[4,3-a]quinoxaline Following the method of Example 11, the 4-chloro[1,2,4]triazolo[4,3-a]quinoxaline used here (product of Example 2) and 4 as starting material instead of di-n-propylamine, respectively.
-Chloro-1-ethyl[1,2,4]triazolo[4,3-a]quinoxaline (product of Example 4)
The crude product was recrystallized from cyclohexane to give 3.54 g (69% yield) of pure 4-diethylamino-1-ethyl[1,2,4]triazolo[4,3-a]. Quinoxaline is obtained as a white solid. (mp98~100
℃). Mass spectrum: m/e, 269 (P). Example 19 4-isopropylamino-1-ethyl [1,
2,4]Triazolo[4,3-a]quinoxaline 4-chloro-1-ethyl[1,2,4]triazolo[4,3-a]quinoxaline (2.3 g,
0.01 mol) (product of Example 4) is added isopropylamine (1.77 g, 0.03 mol). 30
A precipitate forms within minutes. The reaction mixture is stirred overnight at room temperature. The precipitate is collected by filtration and washed with N,N-dimethylformamide. Recrystallization from ethanol yielded 1.6 g (63% yield) of 4-isopropylamino-1-ethyl[1,2,4]triazolo[4,
3-a] Obtain quinoxaline. mp222−4℃.
Mass spectrum: m/e, 255 (P) Elemental analysis: As C ₁₄ H ₁₇ N ₅ Calculated value: C, 65.86; H, 6.71; N, 27.43 Actual value: C, 65.32; H, 6.76; N, 27.25 Implemented Example 20 4-ethylamino-1-isopropyl [1,
2,4]triazolo[4,3-a]quinoxaline in N,N-dimethylformamide (15 ml)
A slurry of 1.0 g (0.004 mol) of 4-chloro-1-isopropyl[1,2,4]triazolo[4,3-a]quinoxaline (product of Example 6) was saturated with monoethylamine gas and stirred at room temperature. Stir for 4 hours. The precipitate was collected by filtration and washed with N,N-dimethylformamide to obtain 220 mg (22% yield) of 4-ethylamino-1-isopropyl[1,2,4]triazolo[4,3-a]quinoxaline. .
mp209-211℃, mass spectrum: m/e, 255
(P). Pour the liquid into ice and filter to remove the precipitate.
Wash with water. Recrystallized from methanol and then from isopropanol to give 200 mg (20% yield) of pure,
4-ethylamino-1-isopropyl [1,2,
4] Obtain triazolo[4,3-a]quinoxaline. mp210−211℃. Elemental analysis: as C ₁₄ H ₁₇ N ₅ Calculated value: C, 65.86; H, 6.71; N, 27.43 Actual value: C, 65.53; H, 6.58; N, 27.29 Example 21 4-diethylamino-1-isopropyl [1 ，
2,4]triazolo[4,3-a]quinoxaline 4 in N,N-dimethylformamide (15 ml)
-Chloro-1-isopropyl[1,2,4]triazolo[4,3-a]quinoxaline (1.0g,
0.004 mol), (product of Example 6) and 900 mg
(0.012 mol) of diethylamine is stirred at room temperature for 4 hours. Pour the reaction mixture into ice and filter to remove the precipitate. After washing with water, it was placed on a silica gel (175 ml) column and finally eluted with chloroform. The effluent was distilled off under vacuum to give 850 mg (75% yield).
Pure, 4-diethylamino-1-isopropyl[1,2,4]triazolo[4,3-a]quinoxaline is obtained as a white solid. (mp93−95
℃). Mass spectrum: m/e283 (P), pure product (100mg) distilled under vacuum at 140-150℃ (0.1mm)
A sample for elemental analysis is then obtained. (80mg), m.
p.94−96℃. _Elemental analysis: _C16H21N5 Calculated value _: C, 67.82; H, 7.47; N, 24.71 Actual value: C, 67.56; H, 7.20; N, 24.50 Example 22 4-diethylamino-1-n-propyl [1,
2,4] triazolo[4,3-a]quinoxaline 4-chloro-1-n-propyl[1,2,4]
Triazolo[4,3-a]quinoxaline (1.23
g, 0.005 mol), (product of Example 5) and 1.1 g
(0.015 mol) of diethylamine is stirred in N,N-dimethylformamide (15 ml) for 1 hour at room temperature. Pour the reaction mixture into ice. A precipitate is obtained by filtration, washed with water and air-dried. ethanol/
Recrystallized twice with water to obtain 1.1 g (78% yield) of pure 4-
diethylamino-1-n-propyl [1,2,
4] Obtain triazolo[4,3-a]quinoxaline. mp92−94℃. Mass spectrum: m/e283
(P) Elemental analysis: As C ₁₆ H ₂₁ N ₅・1/8H ₂ O Calculated value: C, 67.28; H, 7.50; N, 24.52 Actual value: 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 4,8-dichloro-1-ethyl[1,2,
4] Preparation of triazolo[4,3-a]quinoxaline 2,6-dichloro-3-hydrazinoquinoxaline (1.0 g, 0.0044 mol), (product of Preparation Example L(a))
is refluxed with 15 ml of triethylorthopropionate for 4 hours. Cool this to room temperature. Remove the precipitate by filtration, wash with cyclohexane, and air dry.
mg (62% yield) of 4,8-dichloro-1-ethyl[1,2,4]triazolo[4,3-a]quinoxaline is obtained. mp＞250℃, mass spectrum:
m/e, 266 (P); m/e, 268 (P+2). b Production of 8-chloro-4-diethylamino-1-ethyl[1,2,4]triazolo[4,3-a]quinoxaline 4,8-dichloro-1-ethyl[1,2,4]
Triazolo[4,3-a]quinoxaline (7.4g,
0.028 mol) and 6 g (0.082) of diethylamine are stirred in N,N-dimethylformamide (150 ml) at room temperature for 4 hours. Filter the reaction mixture and pour into ice. The precipitate formed is filtered off and dissolved in chloroform. The chloroform layer is dried over anhydrous magnesium sulfate and filtered. Evaporate under vacuum to obtain a colorless solid. Recrystallized from diethyl ether/petroleum ether to yield 1.6 g of pure 8-chloro-4
-diethylamino-1-ethyl[1,2,4]triazolo[4,3-a]quinoxaline is obtained.
mp105−108℃ (decomposition). Mass spectrum: m/
e303 (P); m/e, 305 (P+2) Elemental analysis: C ₁₅ H ₁₈ ClN ₅ Calculated value: C, 59.30; H, 5.97; N, 23.05 Actual value: C, 58.92; H, 5.85; N, 22.81 Example 24 7.8-dichloro-4-diethylamino-1-ethyl[1,2,4]triazolo[4,3-a]
Quinoxaline a Production of 2,6,7-trichloro-3-hydrazinoquinoxaline 2,3,6,7-tetrachloroquinoxaline (4.4 g, 0.016 mol) and 1.76 g (0.035 mol) of hydrazine hydrate were dissolved in ethanol (60 ml). ) Stir overnight at room temperature. Filter the thick slurry and wash with ethanol to obtain 4.9 g of crude 2,6,7-trichloro-3-hydrazinoquinoxaline. mp<
260℃. Mass spectrum: m/e, 262 (P); m/e (P+
2) b 4,7,8-trichloro-1-ethyl [1,
Preparation of 2,4]triazolo[4,3-a]quinoxaline 2,6,7-trichloro-3-hydrazinoquinoxaline (4.9 g, 0.018 mol) was dissolved in triethylorthopropionate (50 ml) at 100°C for 2 hours. Heat for an hour. The precipitate formed is filtered off at room temperature and washed with cyclohexane. Recrystallized twice from chloroform/cyclohexane to obtain 2.9 g (54% yield) of pure, 1,
7,8-trichloro-1-ethyl [1,2,4]
Triazolo[4,3-a]quinoxaline is obtained as a pink solid (mp 198-201°C). Mass spectrum: m/e300 (P); m/e302 (P+
2); m/e304 (P+4); m/e306 (P+6). c 7,8-dichloro-4-diethylamino-1
-ethyl[1,2,4]triazolo[4,3-
a] Production of quinoxaline 4,7,8-trichloro-1-ethyl [1,
2,4]triazolo[4,3-a]quinoxaline (2.9 g, 0.0096 mol) and 2.1 g (0.0388 mol) of diethylamine are stirred in N,N-dimethylformamide (50 ml) at room temperature for 2 hours. Pour the reaction mixture into ice and stir for 15 minutes. Remove the precipitate by filtration, wash with water, and air dry. Recrystallized three times from isopropanol to obtain 500 mg (16% yield) of pure 7,8
-Dichloro-4-diethylamino-1-ethyl[1,2,4]triazolo[4,3-a]quinoxaline is obtained. mp147−149℃. Mass spectrum: m/e, 337 (P); m/e 339 (P
+2) _Elemental analysis _{: C15H17Cl2N5} Calculated value _: C, 53.26; H, 5.07; N, 20.70 Actual value: C, 53.05; H, 5.13; N, 20.75 Example 25 4-diethylamino-1 -Ethyl-8-methoxy[1,2,4]triazolo[4,3-a]quinoxaline a Production of 2-chloro-3-hydrazino-6-methoxyquinoxaline 2,3-dichloro-6-methoxyquinoxaline (4.2g , 0.018 mol), (product of Preparation Example E(b)),
2.7 ml of hydrazine hydrate is heated to reflux in 100 ml of ethanol for 4 hours. After stirring overnight at room temperature, the precipitate is filtered off. Wash with ethanol,
3.9 g (97% yield) of 2-chloro-3-hydrazino-6-methoxyquinoxaline are obtained. mp<
250℃, mass spectrum; m/e, 224(P); m/
e226 (P+2). b Production of 4-chloro-1-ethyl-8-methoxy[1,2,4]triazolo[4,3-a]quinoxaline 2-chloro-3-hydrazino-6-methoxyquinoxaline (1.3 g, 0.0058 mol) 25 ml of triethylorthopropionate at 100°C.
Heat for 60 hours and stir at room temperature for 60 hours. Remove the precipitate by filtration and wash with ethanol. Recrystallized from ethanol to yield 530 mg (35%) of pure 4-chloro-1
-Ethyl-8-methoxy[1,2,4]triazolo[4,3-a]quinoxaline is obtained. mp196
-198℃ (decomposition). Mass spectrum: m/e262
(P); m/e264 (P+2). c 4-dimethylamino-1-ethyl-8-methoxy[1,2,4]triazolo[4,3-a]
Production of quinoxaline 4-chloro-1-ethyl-8-methoxy [1,
2,4]triazolo[4,3-a]quinoxaline (520 mg, 0.002 mol) and 673 mg (0.008 mol) of diethylamine were dissolved in N,N-dimethylformamide.
Stir overnight at room temperature in 10 ml. Pour the reaction mixture into ice and filter to remove the precipitate. Wash with water, air dry, and recrystallize from diethyl ether and petroleum ether. 140 mg (23% yield) of pure 4-diethylamino-1-ethyl-8-methoxy [1,2,4]
A triazolo[4,3-a]quinoxaline is obtained.
mp135−138℃. Mass spectrum: m/e299 (P) Elemental analysis: as C ₁₆ H ₂₁ N ₅ O・1/8H ₂ O Calculated value: C, 63.71; H, 7.10; N, 23.22 Actual value: C, 63.63; H, 6.88 ;N, 23.37 Example 26 4-diethylamino-1-phenyl [1,2,
4] Triazolo[4,3-a]quinoxaline a Production of 4-chloro-1-phenyl[1,2,4]triazolo[4,3-a]quinoxaline 2-chloro-3-hydrazinoquinoxaline (2.2g, 0.011 mol) with 6 ml of triethylorthobenzoate and heated at 100° C. for 30 minutes.
Cool the orange mixture to room temperature and add ethanol. Filter the precipitate and triturate 2.1 g of product with hot methanol and filter. Air dried 1.58g (51%)
Pure, 4-chloro-1-phenyl [1,2,4]
The triazolo[4,3-a]quinoxaline is obtained as an orange solid. b 4-diethylamino-1-phenyl [1,
Preparation of 2,4]triazolo[3,2-a]quinoxaline 1.58 g (0.00563 mol) of 4-chloro-1-phenyl[1,2,4]triazolo[4] dissolved in 15 ml of N,N-dimethylformamide. , 3-a]
Add 1.738 ml of diethylamine to the quinoxaline solution. The mixture is stirred overnight at room temperature and the precipitate formed is filtered off. Washing with N,N-dimethylformamide and recrystallization from hexane/ethyl acetate (3:1 volume) yielded 555 mg of pure 4-diethylamino-1-phenyl[1,2,4]triazolo[4,
3-a] Quinoxaline is obtained as white needle-like crystals.
(mp166−168℃). Elemental analysis: C ₁₉ H ₁₉ N ₅ Calculated value: C, 71.60; H, 5.99; N, 22.06 Actual value: C, 71.86; H, 5.86; N, 22.09 Example 27 4-diethylamino-1-trifluoromethyl [1,2,4]triazolo[4,3-a]quinoxaline a Preparation of 4-hydroxy-1-trifluoromethyl[1,2,4]triazolo[4,3-a]quinoxaline Drying with flame and cooling with ice 22.8 g (0.20 mol) of cold trifluoroacetic acid is placed in a reaction flask placed in a bath under dry nitrogen gas. Under stirring, 2-chloro-
Add 3-hydrazinoquinoxaline (3.89 g, 0.02 mole) (product of Example 1). 100 mixture
Heat at ℃ for 3 hours and pour into ice. The product is filtered off with suction, washed with water and air dried. 3.0g
(60%) pure, 4-hydroxy-1-trifluoromethyl[1,2,4]triazolo[4,3-
a] Obtain quinoxaline. mp＞300℃Mass spectrum: m/e254(P) b 4-chloro-1-trifluoromethyl [1,
Preparation of 2,4]triazolo[4,3-a]quinoxaline In a flame-dried reaction flask, 3.0 g
(0.0118 mol) of 4-hydroxy-1-trifluoromethyl[1,2,4]triazolo[4,3-
a] Quinoxaline and 30 ml of phosphorus oxychloride;
2.38 g (0.0236 mol) triethylamine (3.3
ml) under nitrogen gas. Reaction mixture at 100℃
Cook for about 16 hours (i.e. overnight). The mixture is cooled to room temperature and concentrated under vacuum. This is partitioned between ice, water and ethanol and extracted with ethyl acetate.
The extract is washed with saturated saline and dried over anhydrous magnesium sulfate. The desiccant was removed by filtration, and the solvent was distilled off under reduced pressure. The resulting residue is dissolved in hot chloroform and filtered. The solution is left overnight at room temperature and filtered again. The liquid is concentrated under vacuum to obtain 1.4 g of 4-chloro-1-trifluoromethyl[1,2,4]triazolo[4,3-a]quinoxaline as a brown solid. c Preparation of 4-diethylamino-1-trifluoromethyl[1,2,4]triazolo[4,3-a]quinoxaline 700 mg (0.0025 mol) of 4-chloro-1-trifluoromethyl[1,2,4] Triazolo [4,
3-a] Quinoxaline (produced as described above),
A mixture of 560 mg (0.0075 mol) diethylamine, 10 ml N,N-dimethylformamide is stirred at room temperature overnight and poured into ice. The solid product obtained by filtering the mixture is washed with water and dissolved in ethyl acetate. This is washed with saturated saline and dried over anhydrous magnesium sulfate. The desiccant was removed by filtration, and the solvent was distilled off under reduced pressure to obtain a pale yellow solid. Recrystallization from diethyl ether yields pure 4-diethylamino-1-trifluoromethyl[1,2,4]triazolo[4,3-a]quinoxaline. Initially, 260 mg (34%) of product (melting point 155 ~
157 DEG C.) and a second further yield of 170 mg (22%) of product having a melting point of 153 DEG-156 DEG C. Elemental analysis: as C ₁₄ H ₁₄ F ₃ N ₅ Calculated value: C, 54.37; H, 4.56; N, 22.64 Actual value: C, 54.08; H, 4.47; N, 23.32 Example 28 4-isopropylamino-1- Trifluoromethyl[1,2,4]triazolo[4,3-a]
Quinoxaline 700 mg (0.0025 mol) of 4-chloro-1-trifluoromethyl[1,2,4]triazolo[4,
3-a] Quinoxaline (Example 27b), 443 mg
(0.0075 mol) of isopropylamine (0.64 ml),
A mixture of 10 ml of N,N-dimethylformamide is stirred at room temperature overnight and then poured into ice. The mixture is filtered and the solids are washed with water and then dissolved in diethyl ether. The ether solution is washed with saturated brine and dried over anhydrous magnesium sulfate. The drying agent is removed by filtration, and the solvent is distilled off under reduced pressure to obtain a white powder. Recrystallize from diethyl ether, 550mg
(74%) of pure 4-isopropylamino-1-trifluoromethyl[1,2,4]triazolo[4,
3-a] Obtain quinoxaline. mp185−187℃. Elemental analysis: as C ₁₃ H ₁₂ F ₃ N ₅ Calculated value: C, 52.88; H, 4.10; N, 23.72 Actual value: C, 52.73; H, 4.00; N, 23.67 Example 29 1-ethyl-4-( N-ethylacetylamino)
[1,2,4]triazolo[4,3-a]quinoxaline 241 mg (0.001 mol) of 1-ethyl-4-ethylamino[1,2,4]triazolo[4,3-a]
Quinoxaline (product of Example 17), 2.5 g
(0.025 mol) of acetic anhydride (2.5 ml),
Reflux (140° C.) under nitrogen gas for 3 hours in a flame-dried reaction flask. A precipitate forms when cooled to room temperature. The reaction mixture is poured into water and extracted with chloroform. Combine the chloroform extracts,
After washing with water, dry with anhydrous magnesium sulfate. The drying agent is removed by filtration, and the solvent is distilled off under reduced pressure to obtain a solid. Recrystallized from chloroform/diethyl ether to give 160 mg (57%) of 1-ethyl-4-(N-
Ethylacetylamino)[1,2,4]triazolo[4,3-a]quinoxaline is obtained. mp185゜−187℃. Elemental analysis: as C ₁₅ H ₁₇ N ₅ O Calculated value: C, 63.59; H, 6.05; N, 24.72 Actual value: C, 63.17; H, 6.05; N, 24.39 Example 30 4-acetylamino-1-ethyl [1, 2,
4] Triazolo[4,3-a]quinoxaline 533 mg (0.0025 mol) of 4-amino-1-ethyl[1,2,4]triazolo[4,3-a]quinoxaline (product of Example 14), 1.0 (0.01 mol) acetic anhydride (1.0 ml), 20 ml methylene chloride is refluxed overnight (~16 hours). Cool to room temperature and concentrate the clear solution under vacuum to give a white solid. Recrystallization from chloroform/diethyl ether gives 520 mg (82%) of pure 4-acetylamino-1-ethyl[1,2,4]triazolo[4,3-a]quinoxaline.
mp193-195℃ Elemental analysis: as C ₁₃ H ₁₃ N ₅ O Calculated value: C, 61.16; H, 5.13; N, 27.43 Actual value: C, 60.90; H, 5.26; N, 27.66 Example 31 4-Diacetylamino -1-ethyl [1,2,
4] Triazolo[4,3-a]quinoxaline 5.5 g (0.0258 mol) of 4-amino-1-ethyl[1,2,4]triazolo[4,3-a]quinoxaline (product of Example 14), 25g (0.25mol)
of acetic anhydride, 100 mg of p-dimethylaminopyridine in 60 ml of pyridine is stirred at room temperature overnight (~18 hours). Filter the resulting slurry,
Exclude insoluble matter. The liquid is distilled off under high vacuum to give a dark gummy residue. When water is added, pink-white crystals are obtained. This was collected by suction, washed with a large amount of water, and dried under vacuum at 50°C to give 2.9 g (38%) of 4-diacetylamino-1-ethyl [1,2,
4] Obtain triazolo[4,3-a]quinoxaline. mp157−159℃. Recrystallize with ethyl acetate/diethyl ether to obtain a sample for elemental analysis (mp158
-160℃). The pure product was confirmed by mass spectrometry, nuclear magnetic resonance data, and elemental analysis. Mass spectrum: m/e297 (P) Elemental analysis: as C ₁₅ H ₁₅ N ₅ O ₂ Calculated value: C, 60.59; H, 5.09; N, 23.56 Actual value: C, 60.33; H, 5.09; N, 23.41 Implemented Example 32 Using the methods described in the Preparations and Examples above, and using readily available materials as starting materials in each of the following cases, the following products [1, 2,
4] Triazolo[4,3-a]quinoxaline-4
- producing an amine derivative; 7,8-dibromo-4-diethylamino [1,
2,4]triazolo[4,3-a]quinoxaline, mp199-201°C. 8-chloro-4-isopropylamino [1,
2,4] triazolo[4,3-a]quinoxaline, mp177-181℃ 4-ethylamino-1-trifluoromethyl[1,2,4]triazolo[4,3-a]quinoxaline, mp223-225℃ 1 -Ethyl-4-ethylamino-8-methoxy[1,2,4]triazolo[4,3-a]quinoxaline, mp234-237℃ 4-diethylamino-8-methoxy[1,2,
4] triazolo[4,3-a]quinoxaline,
mp124-126℃ 8-chloro-1-ethyl-4-isopropylamino[1,2,4]triazolo[4,3-a]quinoxaline, mp189-191℃ 4-(N-piperazino)[1,2,4 [Triazolo[4,3-a]quinoxaline, mp160-162℃ 8-chloro-4-(N-piperazino)[1,2,
4] triazolo[4,3-a]quinoxaline,
mp253-256℃ 8-chloro-1-4-(N-isopropylamino)[1,2,4]triazolo[4,3-a]quinoxaline, mp148-151℃ 4-acetylamino-8-chloro-1- Ethyl[1,2,4]triazolo[4,3-a]quinoxaline, mp203-205℃ 8-chloro-1-ethyl-4-(N-isopropylacetylamino)[1,2,4]triazolo[4, 3-a] Quinoxaline, mp155-158℃ 7,8-dichloro-4-(N-isopropylacetylamino)[1,2,4]triazolo[4,
3-a] Quinoxaline, mp207-210℃ 4-Amino-7,8-dichloro-1-ethyl[1,2,4]triazolo[4,3-a]quinoxaline, mp>260℃ 4-Amino-8- Chloro-1-ethyl [1,
2,4]triazolo[4,3-a]quinoxaline, mp248-253℃ 4-acetylamino-7,8-dichloro-1-
Ethyl[1,2,4]triazolo[4,3-a]
Quinoxaline, mp230-232℃ 8-Fluoro-4-isopropylamino [1,
2,4] triazolo[4,3-a]quinoxaline, mp215-217℃ 4-ethylamino-8-fluoro[1,2,
4] triazolo[4,3-a]quinoxaline,
mp239-242℃ 1-ethyl-8-fluoro-4-isopropylamino[1,2,4]triazolo[4,3-a]
Quinoxaline, mp209-212℃ 7,8-difluoro-4-isopropylamino[1,2,4]triazolo[4,3-a]quinoxaline, mp218-221℃ 1-ethyl-4-ethylamino-8-fluoro[ 1,2,4] triazolo[4,3-a]quinoxaline, mp231-233℃ 7,8-difluoro-4-ethylamino[1,
2,4] triazolo[4,3-a]quinoxaline, mp208-211℃ 4-diethylamino-8-fluoro[1,2,
4] triazolo[4,3-a]quinoxaline,
mp151-153°C 4-diethylamino-1-ethyl-8-fluoro[1,2,4]triazolo[4,3-a]quinoxaline, mp94-97° 7-chloro-4-dimethylamino-1-ethyl[1 , 2,4] triazolo[4,3-a]quinoxaline methanesulfonate (mesylate), m.
p.214-217℃ 7-chloro-4-diethylamino-1-ethyl[1,2,4]triazolo[4,3-a]quinoxaline methanesulfonate, mp172-175℃ 7,8-dichloro-1-ethyl- 4-(N-piperazino)[1,2,4]triazolo[4,3-
a] Quinoxaline methanesulfonate, mp252
-255℃ 7,8-dichloro-4-dimethylamino-1-
Ethyl[1,2,4]triazolo[4,3-a]
Quinoxaline, mp168-171℃ 7.8-dichloro-4-dimethylamino-1-ethyl[1,2,4]triazolo[4,3-a]quinoxaline methanesulfonate, mp216-219℃ 4-acetylamino-1-ethyl- 8-Fluoro[1,2,4]triazolo[4,3-a]quinoxaline, mp203-205℃ 4-Amino-7-chloro-1-ethyl[1,
2,4]Triazolo[4,3-a]quinoxaline methanesulfonate, mp240-243℃ 7-chloro-1-ethyl-4-ethylamino[1,2,4]triazolo[4,3-a]quinoxaline methanesulfonate , mp187-189℃ 7-chloro-4-diethylamino[1,2,
4] Triazolo[4,3-a]quinoxaline methanesulfonate, mp205-207℃ 4-diethylamino-7,8-difluoro[1,2,4]triazolo[4,3-a]quinoxaline methanesulfonate, mp220-223℃ 4-acetylamino-7-chloro-1-ethyl[1,2,4]triazolo[4,3-a]quinoxaline, mp210-212℃ 8-chloro-1-ethyl-4-ethylamino[1,2, 4] Triazolo[4,3-a]quinoxaline methanesulfonate, mp235-238℃ 4-amino-7-chloro[1,2,4]triazolo[4,3-a]quinoxaline, methanesulfonate, mp279-282℃ 4 -amino-8-chloro-1-methyl[1,
2,4]Triazolo[4,3-a]quinoxaline methanesulfonate, mp213-215℃ 8-chloro-4-isopropylamino-1-trifluoromethyl[1,2,4]triazolo[4,3-a]quinoxaline methanesulfonate,
mp183-185℃ 8-chloro-4-diethylamino-1-methyl[1,2,4]triazolo[4,3-a]quinoxaline methanesulfonate, mp172-175℃ 4-diacetylamino[1,2,4]triazolo [4,3-a] Quinoxaline, mp211-214℃ 4-Diacetylamino-8-chloro[1,2,
4] triazolo[4,3-a]quinoxaline,
mp208-210℃ 8-chloro-4-isopropylamino-1-methyl[1,2,4]triazolo[4,3-a]quinoxaline methanesulfonate, mp206-208℃ 4-acetylamino-1-methyl-8- Chloro[1,2,4]triazolo[4,3-a]quinoxaline, mp262-264℃ 8-chloro-1-ethyl-4-trimethylacetylamino[1,2,4]triazolo[4,3-
a] Quinoxaline, mp211-213℃ 7,8-difluoro-1-ethyl-4-isopropylamino[1,2,4]triazolo[4,3
-a] Quinoxaline methanesulfonate, m.
p.151-152℃ 4-n-butyrylamino-8-chloro-1-ethyl[1,2,4]triazolo[4,3-a]quinoxaline, mp185-187℃ 8-chloro-4-diethylamino-1- trifluoromethyl[1,2,4]triazolo[4,3
-a] Quinoxaline, hydrate, mp135-
136℃ 4-amino-8-chloro-1-trifluoromethyl[1,2,4]triazolo[4,3-a]quinoxaline methanesulfonate, mp259-261℃ 4-ethylamino-8-fluoro-1-tri Fluoromethyl[1,2,4]triazolo[4,3
-a] Quinoxaline methanesulfonate, m.
p.180-183℃ 8-Fluoro-4-isopropylamino-1-
trifluoromethyl[1,2,4]triazolo[4,3-a]quinoxaline methanesulfonate,
mp185−188℃ 4-diethylamino-7,8-difluoro-1
-ethyl[1,2,4]triazolo[4,3-
a] Quinoxaline, mp109-111℃ 1-ethyl-4-ethylamino-7-fluoro[1,2,4]triazolo[4,3-a]quinoxaline methanesulfonate, mp215-219℃ 4-amino-7-methoxy [1,2,4]Triazolo[4,3-a]quinoxaline methanesulfonate, mp262-264℃ 8-chloro-4-isopropylamino-1-phenyl[1,2,4]triazolo[4,3-a]
Quinoxaline, mp183-186℃ 8-chloro-4-ethylamino-1-phenyl[1,2,4]triazolo[4,3-a]quinoxaline, mp254-256℃ 7-fluoro-4-isopropylamino[1,
2,4] triazolo[4,3-a]quinoxaline methanesulfonate, mp214-216℃ 1-ethylamino-7-fluoro[1,2,
4] Triazolo[4,3-a]quinoxaline methanesulfonate, mp216-218℃ 1-diethylamino-8-fluoro-1-trifluoromethyl[1,2,4]triazolo[4,
3-a] Quinoxaline, mp146-149℃ 7,8-dichloro-1-ethyl-4-isopropylamino[1,2,4]triazolo[4,3-
a] Quinoxaline, mp197-198℃ 8-chloro-4-diethylamino-1-phenyl[1,2,4]triazolo[4,3-a]quinoxaline, mp194-195℃ 1-acetylamino-1-ethyl-7 -Fluoro[1,2,4]triazolo[4,3-a]quinoxaline, mp273-275℃ 1-acetylamino-8-chloro-1-trifluoromethyl[1,2,4]triazolo[4,3]
-a] Quinoxaline, mp215-216℃ 4-amino-8-chloro-1-phenyl [1,
2,4]triazolo[4,3-a]quinoxaline methanesulfonate, mp273-275℃ 8-chloro-4-ethylamino-1-trifluoromethyl[1,2,4]triazolo[4,3-
a] Quinoxaline, mp228-230℃ 1-ethyl-7-fluoro-4-isopropylamino[1,2,4]triazolo[4,3-a]
Quinoxaline methanesulfonate, mp178−181
°C 4-amino-8-fluoro-1-trifluoromethyl[1,2,4]triazolo[4,3-a]
Quinoxaline hydrochloride, mp260-263℃ 8-chloro-1-ethyl-4R-phenylisopropylamino[1,2,4]triazolo[4,
3-a] Quinoxaline, mp155-157℃ 4-amino-1-ethyl-7-fluoro[1,
2,4] triazolo[4,3-a]quinoxaline, mp285-289℃ 4-amino-1-ethyl-7-methoxy[1,
2,4]Triazolo[4,3-a]quinoxaline methanesulfonate, mp255-258℃ 4-acetylamino-8-fluoro-1-trifluoromethyl[1,2,4]triazolo[4,
3-a] Quinoxaline, mp217-219℃ 4-acetylamino-1-ethyl-7-methoxy[1,2,4]triazolo[4,3-a]quinoxaline, mp202-205℃ 8-chloro-1-ethyl -4S-phenylisopropylamino[1,2,4]triazolo[4,
3-a] Quinoxaline, mp156-157℃ 4-acetylamino-8-fluoro[1,2,
4] triazolo[4,3-a]quinoxaline,
mp240-242℃ 4-acetylamino[1,2,4]triazolo[4,3-a]quinoxaline, mp269-272℃ 4-amino-7-fluoro[1,2,4]triazolo[4,3-a] ] Quinoxaline methanesulfonate, mp246-248℃ 4-amino-8-fluoro[1,2,4]triazolo[4,3-a]quinoxaline methanesulfonate, mp176-178℃ 4-acetylamino-7-fluoro[1, 2,
4] triazolo[4,3-a]quinoxaline,
mp290-292℃ 8-chloro-4-isopropylamino-1-pentafluoroethyl[1,2,4]triazolo[4,3-a]quinoxaline, mp171-174℃ Example 33 8-chloro-1-ethyl- 4-Propionylamino[1,2,4]triazolo[4,3-a]
Quinoxaline 1.25 g (0.005 mol) of 4-amino-8-chloro-1-ethyl[1,2,4]triazolo[4,
3-a] A mixture of quinoxaline (mp 248-253°C), (product of Example 32), 15 ml of propionic anhydride is refluxed overnight for about 16 hours. Then at room temperature (~20
℃) and filter the mixture. The resulting precipitate is dissolved in chloroform and filtered. next,
Wash sequentially with water, saturated sodium bicarbonate water, and saturated saline, and dry over anhydrous magnesium sulfate. The drying agent is removed by filtration, and the solvent is concentrated under reduced pressure. The residue is chromatographed through a 150 ml silica gel column with chloroform/methanol (95:5 by volume). The fractions containing the product are combined and concentrated under vacuum to give crystals. Recrystallize from chloroform/ethyl ether
540 mg (36%) pure, 8-chloro-1-ethyl-
4-Propionylamino[1,2,4]triazolo[4,3-a]quinoxaline is obtained. mp212
−215℃. Elemental analysis: as C ₁₄ H ₁₄ ClN ₅ O Calculated value: C, 55.36; H, 4.64; N, 23.06 Actual value: C, 54.91; H, 4.59; N, 22.76

Claims (1)

[Claims] 1 Formula: (X and X ¹ in the formula are each hydrogen, fluoro,
selected from the group consisting of chloro, bromo and methoxy; R ₁ selected from the group consisting of hydrogen, lower alkyl, lower perfluoroalkyl and phenyl;
and R ₂ and R ₃ are each selected from the group consisting of hydrogen, lower alkyl, phenylalkyl in ^which the alkyl moiety has up to 3 carbon atoms, and alkanoyl having 2 to 5 carbon atoms; When R ₁ is hydrogen or methyl, at least 1 of R ₂ and R ₃
from a [1,2,4]triazolo[4,3-a]quinoxaline-4-amine base with one always other than hydrogen; or when R ₂ and R ₃ are bonded together to form a piperazino ring); and pharmaceutically suitable acid addition salts thereof. 2 X and X ¹ are each hydrogen, R ₁ is hydrogen, R ₂ and R ₃
A compound according to claim 1, wherein each is lower alkyl. 3. The compound according to claim 1, wherein X and X ¹ are each hydrogen, R ₁ is ethyl, and R ₃ is lower alkyl. 4. The compound of claim 3, wherein R ₂ is hydrogen and R ₃ is ethyl. 5 X and X ¹ are each hydrogen, R ₁ is lower alkyl,
A compound according to claim 1, wherein R ₃ is acetyl. 6. The compound according to claim 1, wherein at least one of X and X ¹ is fluoro, R ₁ and R ₂ are each hydrogen, and R ₃ is lower alkyl. 7 At least one of X and X ¹ is chlorine, R ₁ is lower alkyl or trifluoromethyl, R ₂ is hydrogen,
The compound according to claim 1, wherein R ₃ is hydrogen, lower alkyl, or alkanoyl having 2 to 5 carbon atoms. 8 At least one of X and X ¹ is fluorine, R ₁
is trifluoromethyl, R ₂ is hydrogen, R ₃ is hydrogen,
The compound according to claim 1, which is lower alkyl or alkanoyl having 2 to 5 carbon atoms.