Note : Les descriptions sont présentées dans la langue officielle dans laquelle elles ont été soumises.
BRIEF SUMMARY OP THE INVENTION
This invention relates to new organic compounds
and, more particularly, is concerned with novel substituted
6-phenyl-1,2,4-triazolo[4,3-b3pyridazines which may be
represented by the followin~ structural formula:
~ R3
R4
wherein Rl, R2, and R3 are each individually selected from
the group consisting of hydrogen and alkyl having up to 3
carbon atoms; and R4 is~ o~o, bromo, fluoro, cyano, tri-
fluoromethyl, nitro, amino, acetamido, carbamoyl, thiocar-
bamoyl or alkyl having up to 4 carbon atoms with the first
proviso that at least one of R1 and R2 is hydrogen, and
with the second proviso that when R1, R2 and R4 are
all hydrogen then R3 may not be methyl, and with the third
j proviso that when R2 and R3 are both methyl then R1 and R4
may not be hydrogen. The invention also includes novel com-
positions of matter containing the above-defined compounds
useful as anxiolytic agents and the method of meliorating
anxiety in mammals therewith.
The novel compounds of ~he presPnt invention are
generally obtainable as white to pale yellow crystalline
materials having characteristic melting points and absorption
spectra and which may be purified by recrystallization from
common organic solvents such as methanol, ethanol, dimethyl-
formamide, acetone, chloroform, ethyl acetate, and the like.
They are appreciably soluble in non-polar organic solvents
such as toluene, carbon tetrachloride, and the like but are
relatively insoluble in water. The organic ba~es of this in-
; vention form non-toxic acid-addition salts with a variety of
pharmacologically acceptable organic and inorganic salt-form-
ing reagents. Thus, acid-addition salts, formed by admixture
of the organic free base with one or two equivalents of an
.~.l' ,. ,_ ~
' ' ~ ', .
acid, suitably in a neutral solvent, are formed with such
acids as sulfuric, pho~phoric, hydrochloric, hydrobromic, s~l-
famic, citric, lactic, malic, succinic, tartaric, acetic, ben-
zoic, gluconic, ascorbic, and the like. The acid-addition
salts are relatively insoluble in non-polar organic solvents
Ruch as diethyl ether, benzene, toluene, and the like but are
appreciably soluble in water. For purpo~e~ of this invention,
the free baseq are equivalent to their non-toxic acid-addi-
tion Ralts.
The novel compounds of the present invention may be
readily prepared in accordance with the following reaction
~cheme~
~ 2 (hydrazine) R1 ~
R4-CH-CH-C02EI ~ - ~ ~ ~ N
(I) R~
~II)
~bromine)
~2 R2
Rl ~ C1 1 ~ O
(phosphorus ~ -
N ~ oxychloride) ~ NH
(IV) 4 (III)
11
25 - (H2N-NH-C-R3)
(V) R2
~ ~ 3
.
wher~in Rl, R2, R3, and R~ are as hereinabove defined. In
accordance with th~ above reaction schema, an appropriately
substituted 3-benzoylpropionic acid (I) is reacted with hydra-
zine hydrate at ~he reflux temperature in a lower alkanol
solvent for a period of 12-24 hours to provide the corre~-
ponding 4,5-dihydro~6-phenyl-3(2~)-pyridazinone (II). Treat-
ment of the 4,5-dihydro-6-phenyl-3(2H)-pyridazinone (II) with
bromine in glacial acetic acid solvent at steam bath tempera-
ture for a period of 2~4 hours provides the corresponding 6-
-phenyl-3(2H)-pyridazinone (III). Conver~ion of the 6-phenyl-
-3~2H)-pyridazinone (III) to the corresponding 3-chloro-6-
-phenylpyridazine (IV) is achieved by treatment with excess
pho~phoru~ oxychloride at steam bath temperature for a period
of 4-8 hours. Int0raction of the 3-chloro-6-phenylpyridazine
(IV) with an acylhydrazine (V) a~ the reflux ~emperature in a
lower alkanol solvent for a period of 24-48 hours provides
the corresponding 6-phenyl-1,2,4-triazolo[~,3-b]pyridazines
(VI) of the present invention.
The novel compounds of the present invention may
also be readily prepared in accordance with the following
. reaction ~cheme:
: 25
~ ,
~ 3
2 R%
Rl ~ NH-NH2 Rl ~ Cl
,--_
~4 ~ N 4~` N
~ ~1~, ~
~N
R4 (VIII)
R
R ~ ~ N ~
~ N 1~ alkyl
(IX)
~.:
wherein Rl, R2, and R4 are a~ hereinabove defined. In accor-
dance with the above reaction ~cheme, an appropriately subs~
tuted 3-chloro-6-phenylpyridazine (IV) is reacted with hydra-
zine hydrate at the reflux temperature in a lower alkanol ~ol-
vent for a period 12-24 hour3 to provide the corresponding
3-hydrazino-6-phenylpyridazine (VII). Ring closure of the
3-hydrazino derivatives (VII) with lower alkyl orthoformate~
provides compounds of formula (VIII) wherein R3 i8 hydro~en.
Rlng closure of the 3-hydrazino darivative~ (VII) with lower
alkanoic acid anhydrldes, lower alkanoic acid chloride~, or
orthoe~ters of lower alkanoic acid~ pro~ides compounds of
. formula (IX) wherein R3 is lower alkyl. The ring clo~ure~
may be c~rried out w~th or without catalysis by ba~es such
as pyrldine or tri(lower alkyl~ amine~. Ring clo~ures with
lower alkyl orthoformates and orthoe ~er~ of lower alkanoic
: - 4 -
:
acids are prefexably carried out without catalysis and with-
out solven~, although an inert solvent may be used. ~he ring
closures are usually accomplished by heating with or without
a solvent at 50C. to 175C.
The novel compounds of the pre~ent invention posses3
anti-hypertensive activity at non-toxic doses and as ~uch are
useful as hypotensive agents. The compounds have been tested
pharmacologically and found to have such properties with a de-
sirable wide spread between doses producing lowered blood
~ressure and toxic symptoms. The hypotensive properties of
the compounds of the present invention have been shown when
orally administered to mammals, specifically warm-blooded
animals, a~ follows: Conscious, normotensive male albino
Wistar strain rats averaging approximately 250 grams were fas-
tened to rat boards in a supine position by means of canvas
and limb ties. The femoral areas were anesthetized (subcu-
taneous infiltration of lidocaine), and the left or right com-
mon iliac arteries were exposed and clamped off proximally
by an artery clamp and distally with thread. Incisions were
made near the tie and short nylon catheters were inserted and
tied in place. The other end of the catheters were fitted
with 24 gauge hubless needles attached to thick-walled poly-
ethylene tubes. The test compounds were administered to the
animals orally, by gavage (stomach tube). The compounds were
tested at 100 mg./kg. and were suspended or dis~olved in 2%
aqueou~ starch solution, 0.2 ml. of which gave, per 100 gram~
of body weight, the desired dose~ ~ean arterial blood pres-
sure was meaaured 4 hour~ and 24 hours after administration
of the compounds. Comparisons were then made to the mean con-
trol pressure of 122 mm. of mercury, which i~ the average of
a number of controls recorded over months of testing. Blood
pressure measurements were made with eight Sta~ham P23 Db
s~rain gauges (Statham Instruments, Inc , Los Anyeles, Cali-
-- 5 --
~a~æ
fornia), attached to a Beckman Dynograph Recorder equipped
with eight strain ~auge preamplifiers with averagin~ circuits
for measuring mean arterial blood pressure. The results with
representative compounds of the present invention appear in
Table I below.
The novel compounds of the present invention were
also tested for antihypertensive activity in a procedure using
spontaneously hypertensive rats (SHR) as follow~: One male
adult ~16-20 weeks old) about 300 grams SHR (Taconic Farms,
Germantown, N.Y.) is dosed by gavage with the test compound
at 100 mg./kg. with or without 0.9% sodium chloride loading
at 25 ml./kg. at 0-hour. A second identical dose is given at
24 hours and the mean arterial blood pressure (MABP) of con-
scious rats is measured directly by femoral artery puncture
at 28 hours~ The results of this test with representative
compounds of the present invention also appear in Table I
below.
- 6 -
~v~ - -- -~-- -
~V~ 1''1 1 1 lU I
o~
Q:
~0 ~: . _ ., : '
~ ~ ~ 5: o ~ ~ U~
K ~ m N .-1 ~n ~1 a~
,c, z~ c al t~ . _ ,~
~1 \\ ~ ~O ~ U~ ~ ~ ~ U~
1-1 ~' ~--Z ~1 ~ 0 Cl~ O O O~ O~
. ~ \Z Zi~$P. ~ r-l_ _l _
P~ bl
a r 11 ~ ~ o o o s~
8 ~ 8
' ~; o o .~ ~ ,.,
~ ~ ~t R
~1 _ __ .. _
v ~ ~ :c ::: ~
~ :~ ~ ~: ~c
- - ~ u~ - -
~v7~Z
J~o __ _ _
~$_
rIQ5
~d b ~ ~ oo ~ ~ o
P~ ~ co o~o ~1 ~1
~0 ~ ~ ~1
a
~'
~ !
~ _ __ _ _
~8 ~ ~;
~ m t:c :~ ul o
a~ ~r ~1
_ I ~ ~ a) _ , . _ _
~ ~ h ~:1
~ o ~ ~n ~:
.~ ~ ~ ~ 3:: o o
O ~ , ~r _ ~1 ~1 _ '
H ti~
~ ~ O O O O O O O
.U~ ~ O O ~ O O O O
~ ~ _~ ~1 ~_1 ~ ~_1 -1 ~
_ _ O _ 0~ ~ O
O ~ ~ 0~ ~ ~0 ~ O
~r ~ ~ ~ ,~ ~ O O ,~
1~ r-l ~ ~ ~ ~: ~1 O ~J ~
U U r~ ~ ~ r~ ~ O
o l
~ ~ ~ ~ I__ ~r ' .~
Q _ _
~ ~:~ m :~: :~: c~ :r ~: ~
_ . ~1 __ _ _
~ m ~ ~ tr: ~ m ~
_ _ ._.
_ ~ m :1: ~ _ ~ . _ _
-- 8 --
~ - - - -
~o-
h ~ ~
a) ,~--~: O ~ 00 O O ~r o~ ~o
Q. )~ o~ ~ ~ n u~ ~D el~ ~
O R = ~`1 ,_1 ,_1 _I r~l ~1 ~1 r-l
_ ~_
tr; m P~ ~r
~ ~ a ~ ~ _ _
.~ ~0~U~ ~4 ~
O) ~
~: O 1~l h ~r r-l
C.) ~ P~ _ _ ___ __
H
~3 O~
o o o o O O o
U~ O O ~ o O o O
E-~ i~3 ~ ,1 ,1 _1 ,_1 _~ ~1 ,_
.
, _ _ __ _ __ _ _
O O
h ~ O O O O
O O h h ~1 O ~1
~ 1 :~ ~1 O O O ~ O
~;~ ~ ~ ~ ~ ~ ~ ~ .~
,1 ~ ~,1 ~ O ~ ~ ~ O
. LJ al ~ a~
E3 ~ er ~r ~ ~ :~
_ _
A _ __ I h
V P
o ~ ~ ::c :~ ~~ e~ ~ ,~
O _ _ _ ~ - . _ _ _ h
~`I ~ ~ O
~; ~: ~ c,) ~ ~ ec tr~
_ _ _ _ _
_ ~ ~ ~ ~ ~ __ ~
The novel compound~ of the present invention have thus been
found to be highly u~eful for lowering elevated blood pres-
sure in mammals when administered in amount~ ranging from
about l.O milligram to about 25.0 mg. per kilogram of body
weight per day. A preferred do~age regimen fox optimum re-
sults would be from about 5.0 mg~ to about 1~.0 mg. per kilo-
gram of body weigh~ per day, and such do~age units are em-
ployed that a total of from about 0.35 gram to about l.O gram
of active compound for a 3ubject of about 70 kg. of body
weight are administered in a 24 hour period. ~he dosage regi-
men may be adjusted to provide thP optimum th~rap~utic re-
sponse. For example, ~everal divided do~e~ may be adminis-
tered daily or the do~e may be proportionally reduced as in-
dicated by the exigencie~ of the therapeutic ~ituation. A
decided practical advantage of this invention is that the
active compounds may be administered in any convenient manner
such as by the oral, intravenou~, intramuscular, or ~ubcutane-
ou~ route~.
The novel compound~ of the present invention have
O been found to be highly useful for meliorating anxiety in mam-
mals when administered in amounts ranging from about 0.03 mil-
ligram to about lO.O mg. per kilogram of body weight per day.
A preferred dosage regimen for optimum results would be from
about 0.1 mg. to about S.O mg. per kilogram of body weight
per day, and such dosage unit~ are employed that a tota-l of
from about 7.0 milligram to about 0.35 gram of active compound
for a 3ubject of about 70 kg. of body weight are administered
in a 24 hour period. This da3age regimen may be adjusted to
provide the optimum therapeutic respon~a. For exampl2, sev-
eral divided dose~ may be admini~tered daily or the doqe may
- 10 -
The novel compounds of the pre3ent invention po~e~
central nervou~ qystem activity at non-toxic do~es and a~
such are u~eful a~ anxiolytic agent8. That is, they produce
certain re~ponqe~ in tandard ts~t~ with laboratory animal~
which are known to correlate well with relief of anxiety in
man. The compounds have been tested pharmacologically and
found to have ~uch properties with a desirable wide ~pread
between do~es producing anxiolytic activity and toxic symptom~.
The anti-anxiety properties of the novel compounds
of ths pre~ent invention have been established in a test which
indicates anxiolytic activity by the measure of protection
from convulsions resulting from the administration of penty-
lenetetrazole. Graded dose levelR of the compound-~ of this
inven~lon were administ~red orally, in a 2~ starch''veh~cl'e,
to groupq of at least 5 rats. At the e~timated time of peak
effect, the rats were treated intravenously with pentylene-
tetrazole at a dose of 21 to 23 mg./kg. of body weight. This
doqe i3 estimated to cau~e clonic ~eizure in 99~ of unpro-
tected rats. The effective dose IEDso) of the te~t compound
~0 for pro~ection o~ 50% of the animals i~ calculated by the
method of D. H. Finney in "Statis~ical Methods in Biological
~ssay", Second Edition, Hafner Publishing Co., New York, 1964,
pp. 456-457. Representative re~ults are given in Table I
which follows in compari~on with chlordiazepoxide or mepro-
bamate, which were te~ted in exactly the ~ame mannar. It has
been reported lR. T. Hill and D. ~. Tedeschi, "Animal Testing
and Screening Procedure~ in Evaluating Psychotropic Drugs"
in "An Introduction to Psychopharmacology", Ed~. R. R. Rech and
K. E. Moore, Raven Press, New York, pp~ 237-288 (1971)~ that
there i~ a high degree of correlation between antagoni~m of
pentylenetetrazole ~eizure8 in rats and anti-anxiety effects
in higher warm-blooded animal~.
~ -
o
,a
o~
.~.
' ~ ~ ~X
N ~ ~1 ~
1~ E3 .
U~ ~ ~
H rl M ~
0(~ ~
_I ~i ~ __
~ ~ ~ : :
E~ ~ ~ .,1
~ ~ ~ ~ O ':
0 ~1 ~ ~ N
~ P~ ~ ~
' ' ' `-~1
m
1-l U ~ O O ~ ~i ~ .
O ~
h O h ,~: `
I
~'' ' '
`,
.
:
- 12 -
!
: ' ' , . ` . .
' ' ' ' ' ~ ~ ' ''` , '
Another test which has been used to assess anti-an-
xiety effects is a non-conditioned passive avoidance procedurs
described by J.R. Vogel, B. Beer and D.E. Clody, "A Simple and
Reliable Conflict Procedure for Testing Anti~Anxiety Agents",
Psychopharmacologia, Vol. 21, pp~ 1-7 (1971). A conflict situa-
tion is induced in rats by a modifica~ion of this method. To
groups of six naive Sprague Dawley rats (200-220 grams), pre-
viously deprived of water for forty-eight hourR and food for
24 hours, are adminis~ered graded oral dose~ of test compound
suspended in 2% starch vehicle also containing 2 drops of poly-
ethylene glycol and polysorbate 80, or vahicle alone (controls).
At the time of peak effect each rat is placed in a plexiglass
box fitted with a drinkometer circuit connected between the
~tainless steel grid floor and a ~tainless steel drinking tube
inserted in a hole in one of the walls of the box. A stimula-
tor supplying monophasic 60 cycle sguare wave pulse~ of 0.2
milliamperes peak intensity, a tim~ which allow~ alternate
5 second "~hock free" and 5 ~econd "shock available" periods
during a 5 minute test period, an electromagnetic counter to
count the number of ~hocks received by the rat during the
shock available period and a delay of one half second between
the successive shocks are incorporated into the drinkometer
circuit. After the rat is placed in the box, it i8 allowed to
explore and drink 10~ dextrose solution ~upplied through the
tap. After twenty seconds of continuous unpuni~hed drinking,
the timer and drinkometer circuits ara activated and 5 3econd
shock Pree and 5 second shock available periods alternate.
The number of shocks received by the rat during a 5 minute
test period i9 recorded. The percentage of rat3 that receive
9 or more shocks in 4 to 5 minutes at each do~e level is used
as positive response in calculation of the median ~ffective
dose tED50). The results of this test on representative com-
pounds of this invention appear in Table II b~low.
- 13 -
7~
~--I
_ ~D~ ,.,
o a~ ,i
,3 ,, ~ ~ :
~,~,1 .
. .'
.~ ~I~r`,O~ ~ . '
8 , ~ N (~
~ _1 o n~ ~3
. ~ . ~ .
~ ~ I . .
",
.
.
li~
TABLE I
Protection A~ainst Clonic Seizures Caused By
Pentylenetetrazole In Rats
~2
N
R3
,
_ . _ _ -~
Compound ~edlan Errectlve
1 - R2 ~= R"~ ~ 9 /
H H H 3-chloro 8. 2
. H H CH3 3-tri-
f luoro- .
methyl 1. 7
H H CH3 4-~luoro 3 . 4
H H H 3-amino 15 '
CH 3 H H 3-cyano 34 . ~:
H H H 4-f luo~o S
H H H 4-chloro 9. 8
H H H 3-tri - . .
f luoro-
. . methyl 2. S
Chlordiazepoxide 2. 5 .
Meprobamate 2~
.
ll - 15 -
. . .
be proportionally reduced as indicated by the exigencies o~
the therapeutic ~ituation. A decided practical advantage of
this invention is that the active compoundR may be admini~-
tered in any convenient mann~r such as by the oral, intraven-
ous, intramu~cular, or subcutanQous routes.
Compositions according to the present invention
having the desired clari~y, stability and adaptability for
parenteral u~e are obtained by dis~olving from 0.10% to 10.0%
by weight of active compound in a vehicle con~isting of a
polyhydric aliphatic alcohol or mixtures thereof. Especially
sati~factory are glycerin, propylene glycol, and polyPthylene
glycol~. The polyethylene glycols consi~t of a mixtur~ of
non-volatile, normally liquid, polyethylene glycols which are
. soluble in both water and organic liquid~ and which have mole-
cular weight~ of from about 200 to lS00. Although the amount
of active compound dissolved in the above vehicle may vary
from 0.10 to 10.0~ by weight, it i~ pre~erred that the amount
of active compound employed be from about 3.0 to about 9.0%
by weight. Although various mixtures of the aforementioned
non-volatile polyethylene glycol~ may be employed, it i5 pre-
~5
30 -
- 16 - -
.
ferred to u~e a mixture having an average molecular weight
of from about 200 to about 400.
In addition to the active compound, the parenteral
solutions may also contai~ various preservatives which may be
used to prevent bacterial and fungal contamination. The pre-
servatives ~hich may be used for thece purpo~es are, for exam-
ple, myristyl-gamma-picolinium chloride, benzalkonium chlo-
ride, phenethyl alcohol, p-chlorophenyl-~-glycerol ether,
methyl and propyl parabens, and ~himarosal. As a practical
matter, it is also convenient to employ antioxidant~. Suit-
able antioxidant~ include, for example, sodium bi3ulfite,
~odium metabisulfite, and sodium formaldehyde suloxylate.
Generally, from about 0.05 to about 0.2% concentrations of
antioxidant are employed.
For intramuscular injection, ~he preferred concen-
tration of active compound is 0.25 to 0.50 mg./ml. of the
finished compositions. The novel compounds of the present
invention are equally adapted to intravenous admini~tration
when diluted with water or diluents employed in intravenous
therapy ~uch a~ isotonic glucoqe in appropriate quantities.
For intravenou3 use, initial concentration down to about
0~05 to 0.25 mg~/ml. of active ingredient are satisfactory.
The active compounds of ~he present invention may
be orally administered, for example, with an inert diluent
or with an assimilable edible carrier, or they may be enclosed
in hard or soft shell gelatin cap~ule~, or they may be com-
pressed into tablets, or thay may be incorporated directly
with the food of the diet. For oral therapeutic administra-
tion, the active compounds may be incorporated with excipient~
and u~od in the form of tablets, ~roche~, cap~ules, elixirs,
su~pensions, syrups, wafers, and the like. Such compo~itions
and preparations ~hould contain at least 0.1% of active com~
poundO The percantage of the compositions and prepara~ions
- 17 -
may, of course, be varied and may conveniently be between
about 2~ to about 60% of the weight of the unit. The amount
of active compound in such therapeutically useful composition~
is such that a suitable dosage will be obtained. Preferred
compositions or preparations according to ~he present inven-
tion are prepared 80 that an oral do~age unit form contains
between about 0.1 and 5.0 milligram3 of active compound.
The tablets, troche~, pill8, cap~ules and the like
may also contain the following: a binder ~uch as gum traga-
canth, acacia, corn starch or gelatin; excipients ~uch as
dicalcium phosphate; a disintegrating agent such as corn
~tarch, potato starch, alginic acid and the like; a lubricant
such as magnesium ~tearate; and a sweetening agent such as
sucrose, lacto e or saccharin may be added or a flavoring
agent such as peppermint, oil of wintergreen, or cherry fla-
voring. When the dosage unit form is a capsule, it may eon-
tain, in addition to material of the above type, a liquid
carrier such as a fatty oil. Various other material~ may be
present as coatings or to otherwise modify the physical form
of the dosage unit. For instance, tablets, pill~, or cap-
~ule~ may be coated with shellac, sugar or both. A ~yrup or
elixir may contain the active compound; sucro~e as a sweeten-
ing agent, methyl and propylparaben~ as preservatives, a dye
and flavoring such a~ cherry or orange flavor. Of course,
~5 any material used in preparing any dosage unit form 3hould
be pharmaeeutically pure and substantially non-toxic in the
amounts employed.
This invention also relate~ to novel substituted
6-phenyl-1,2,4 triazolo[4,3-b]pyridazines u~eful as hypoten-
c~nc/ 6~ X ~ o /~I`c
sive7agents which may be repre~ented by the following structur-
al formula:
- 18 -
R2
R4 \ Rl ~ N
R5 ~ ~ N ~ R3
R6 7
wherein Rl, R2 and R3 are each individually selec~ed from
the group consisting of hydrogen ~nd alkyl having up to 3
carbon atoms with the proviso that at lea~t one of Rl and R2
0 i3 hydrogen; and two of the substituents R4, R5, R6 and R7
are hydxogen and the remaining two are fluoro, chloro, bromo,
methyl, methoxy, nitro, amino or trifluoromethyl. The~e
novel compound~ may be reaily prepared in accordance with the
i reaction schemes hereinabove except that the moiety
R4
a~ therein defined
i~ xeplaced by the moiety
R4
,_
R6 R7
as defined
immediately above. For purpo~e~ of thi~ invention, the~e
I free ba~e~ are equivalent to their non-toxi~ acid-addition
-I salt~-
The invention will be de~cribed in greater detail
in con~unctlon with the following epecific ~xample~.
Prep~r~tlon of ~7-methyl-1,2,4-trlnzolo[4,3-b~pyrid~zin-6-
-yl~henzonitrile
200 g. portion of p-(1,4,5,6-t~ rahydro-4-methyl-
- 19 -
.,
-6-oxo-3-pyridazinyl)benzonitrile [~ournal of Medicinal Chem-
istry 17, 281(1974)] i~ suspended in 500 ml. of glacial acetic
acid with overhead stirring at steam bath temperature, then
56 ml. of liquid bromine i~ dissolved in an additional 500 ml.
of acetic acid and thi~ solution i~ added to the ~tirring
mixture all at once. After approximately hal~ an hour of heat-
ing, a vigorous exothermic reaction occur~ with the expul-~ion
of the excess bromine and hydrogen bromide. The reaction mix-
ture iY then diluted with 4 liter~ of distilled water and the
resulting ~olid is filtered and the filter cake is copiously
washed with water and is air dried. This material i3 recrys-
tallized from a large amount of ethyl alcohol to af~ord the
product ~-(1,6-dihydro-4-methyl-6-oxo-3-pyridazinyl)benzoni-
trile as a white solid.
A 45.9 g. portion of the above material and 25b ml.
o pho~phorus oxychloride is heated at steam bath temperature
for 3 hours. The exce~ phosphoru~ oxychloride is decomposed
by the ~low addition of the reaction mixtura to crushed ice
with stirring. The re~ulting solid is filtered, wa3hed with
water and dried in vacuo. The material is then recry~tallized
from methyl alcohol to give ~-(6-chloro-~-methyl-3-pyridazin-
yl~benzonitrile.
A mixture of 14.6 g. of the above compound, 9.4 g.
of formylhydrazine and 175 ml. of butyl alcohol i~ stirred at
reflux for 18 hour~. Tha reaction mixture i8 concentrated
free of ~olvent and the concentrate i~ trlturated with petrol-
eum ether and i9 iltered. The filter cake i8 air dried and
the yellow solid is recry~tallized twice from methyl alcohol,
the resulting light yellow crystal~ are again re~rystallized
from methanol to afford the product of the example, m.p. 240-
-243C.
_ ~0 --
., ~ .
Exampl~o 2
Preparation of ~-~3,7-dimethyl-1,2,4-triazolo[g,3-b]pyrida~in-
-6-yl)-benzonitrile
A 1.48 g. portion of acetic acid hydrazide is di~-
S Qolved in 50 ml. of butyl alcohol with heating, then 4.58 g.
of ~-(6-chloro-4-methyl-3-pyridazinyl)benzonitrile (prepared
as in Example 1) is added and complete solution occurs after
heating for an additional 10 minute~. The solution is then
heated at reflux for 18 hours. The reaction mixture is con~
centrated to afford 5.8 g. of orange 301id which i8 wa~hed
with petroleum ether. ~hi~ product i9 dissolved in 1:1 ethyl
alcohol/acetone and is filtered through a pad of silica gel.
The filter i~ washed copiously with acetone and the combined
filtrates are concentrated to a yellow solid. The solid is
di~solved in 100 ml. of acetone and the ~olution is cooled in
dry ice-acetone to afford a tan ~olid which is collected by
filtration, wa~hed copiouQly with petroleum ether and air
dried. This product i~ dis~olved in methyl alcohol, i~ treated
with activated chaxcoal and i5 filtered. The filtrate is u~ed
to recry~tallize 1.06 g~ of yellowi~h crystals. A 500 mg. por-
tion of the above iQ recry~tallized twice from methanol and
the resultant product i5 dried in vacuo to give the product of
the example, mOp. 242-244C.
Exam~le 3
Preparation of ~-(3-ethyl-7-methyl-1,2,4-triazolo[~,3-b]pyri-
dazin-6-yl)benzonitrile
A mixture of 102.13 g. of ethyl propionate, 50 g. of
hydrazine hydrate and 150 ml. of ethyl alcohol i8 stirred at
reflux for 24 hour~. The reactlon mixture i~ concentrated
free of ~olvent, then i8 cooled in ice and stirred with petrol-
eum ether. A white solid result9 which 15 filtered, wa~hed
with pe~roleum ether and is dried ln vacuo to afford propionic
acld hydr~zide a~ ~ white crystalllne ~olld.
':
.
A 30.8 ~. portion of the above compound is dissolved
in one liter of butyl alcohol (dried over 3-A molecular
sieves), then 40.0 g. of ~-(6-chloro-4-methyl-3-pyridazinyl)-
benzonitrile (prepared as in Exampl 1) is added and the re-
action mixture is allowed to heat at reflux for 18 hours.
The reaction mixture is concentrated free of ~olvent and the
conc~ntrate i~ triturated with petroleum ether, then is fil-
tered. The filter cake is vacuum dried to afford a yellow
Qolid which is then recry~tallized from methyl alcohol to
give the product of the example, m.p. 192-195C.
Exam~le 4
Preparation of ~-(3-ethyl-7-methyl-1,2,4-triazolo[4,3-b]pyri-
dazin-~-yl~benzamide
~ 4.5 g. por~ion of ~-(3-ethyl-7-methyl-1,2,4-tria-
zolo[4,3-b]pyridazin-6-yl)benzonitrile (prepared a~ described
in Example 3) i8 dissolved in 50 ml. of ethyl alcohol with
warming, then 50 ml. of 30~ hydrogen peroxide is added with
- swirling and finally SO ml. of 2N sodium hydroxide is added
with swirling. mhe reaction is allowed to stand at room tem-
perature for three hours, then is concentrated almost to dry-
nes~ using as little heat as possible The concentrate is
diluted with water, filtered ~nd the filter cake is then washed
with water and air dried~ The product i~ di~olved in acetone
and filtered to remove in~oluble~ then is recr~tallized to
afford a yellow ~olid as the product of the example, m.p.
210-213~C.
Example 5
Preparation of 7-methyl-6-(m-nitrophenyl~-1,2,4-triazolo-
[4,3-b~pyridazine
A 28 g. portion of 3-~m-nitrobenzoyl)butyronitrile
[prepared as described in ~. Org. Chem., Yol. 38, No. 23,
4044-40q8 (1973)] i8 added to one liter of 6N hydrochloric
acid and i~ ~tirred at reflux for one hour u~ing a magnetic
stirrer and a heating mantle. ~he reaction mixture i8 cooled
and extracted with methylene chloride. The organic layer i~
separated and extracted with saturated sodium bicarbonate.
The bicarbonate layer is added dropwise to a stirred cold
hydrochloric acid ~olution and the re~ul~ing ~olid is kept
cold in ice ~hen is fil~ered and air dried to afford 27.24 g.
of 3-m-nitrobenzoyl butyric acid a a white ~olid. The entire
amount of the preceding compound i~ mixed with 12.8 ml. of
99~ hydrazine hydrate in 140 ml. of ethyl alcohol and is
~irred at reflux for 3 hours. A ~olid begin~ to appear after
about half an hour. The reaction mixture is cooled in an ice
bath and the resulting solid is filtered and air dried to af-
ford the compound 4,5-dihydro-5-methyl-6-(m-nitrophenyl)-
-3(2~I)-pyridazinone as white to light yellow cry~tals.
A 24.9 g. portion of the above material i5 dissolved
in 200 ml. of warm stirred glacial acetic acid, then 6.2 ml.
of bromine dissolved in 50 ml. of glacial acetic acid is added
to thi~ dropwi~e ovex a 15 minute period with the evolution
of hydrogen bromide gas~ The reaction mixture i~ warmed for
- an additional 20 minutes to expel the hydrogen hromide, then
the mixture is poured into cru~hed ice. The resulting solid
is filtered and wa-~hed with large amounts of water then is
dried in vacuo to afford 24.2 g. of 5-methyl-6-~m-nitrophenyl)-
-3(2H)-pyridazinone a~ a cream colored ~olid.
A 22.7 g. portion of the preceding compound i8 com-
bined with 230 ml. of phosphorus oxychloride and heated on a
~team bath for 3 hours. The reaction mixture is poured por-
tionwise into crushed ice with stirring. The resulting solid
i8 filtered, copiously washed with water and air dried to
yield 15.6 g. of 3~chloro-5-methyl-6-(_-nitrophenyl)pyridazine
a8 a tan ~olid.
A mixture of 14.97 ~. of ~ha compound above, 7.2 g.
of formylhydrazine and 200 ml. of butyl alcohol i~ 3tirred at
- ?3 -
'
r~flux for 18 hours. The reaction mixture is decanted Eree
of insolubles and the li~uid portion is cooled in an ic~ bath
to afford 13.28 g. of brown cry~alline 301id. This material
is di~solved in 300 ml. of boiling methyl alcohol then i~ fil-
tered to remove insoluble~. The filtrate is clarified by
treatment with activated charcoal and filtering. Thi~ fil-
txate is concentrated to a 3mall volume and cooled to yield
a tan-brown solid a~ the product of the example, m.p. 213-
-218C.
Example 6
Preparation of 6-(m-aminophenyl)-7-me~hyl-1,2,4-triazolo-
.
[4,3-b]pyr_dazine
A mixture comprising 2.28 g. of 7-methyl-6-tm-nitro- :
phenyl)-1j2,4-triazolo[4,3-b]pyridazine (prepared as described
in Example 5), 100 ml. of ethyl alcohol and a catalytic amount
of platinum oxide i8 shaken in a Parr shaker under 40 pounds
of hydrogen pre~ure for 1 1/~ hour~. The reaction mixture
i~ filtered free of cataly~t and the filtrate is concentrated
to afford the product of ~he exa:mple as a yellow solid, m.p.
182-186~C.
Example 7
Prepar~.~ion of 6-(p-bromophenyl)-l~2~4-triazolo[4~3-b]pyrida
.
- z ine
A mixture of 3~76 g. of 3~ bromophenyl)-6-chloro-
pyridazine, 1.80 g. of formylhydrAzine and 50 ml. of butyl
alcohol is heated to reflux. and allowed t~ reflux ov~rnight.
The reaction mixture i8 allowed to cool and the precipitated
product is washed wlth water, air dried and recry~tallized
from methyl alcohol, m.p. 209-211Co
Exam~le ~
PrQparation of 6~ fluorophenyl) -1, , 4-triazolo [4, 3-b] pyri-
dazine
An 87 g..~ample of 6-(~-fluorophenyl)-4,5-dihydro-
'
-3~2H)-pyridazinone (prepared as in United States Patent No.
3,689,652, Example 6) is stirred in 800 ml. of ~lacial acetic
acid in a 2 liter 3 nPcked flask on a steam bathO A solution
of 24.1 ml. of bromine liquid in lO0 ml. of glacial acetic
acid is prepared in a dropping funnelO A 15 ml. portion of
this bromine solution i~ added dropwise to the reaction mix-
ture which is heated with ~tirring until the mixture become~
lighter in color. The remainder of the bromine solution is
then added with heating and ~tixring over about 30 minu~es.
The reaction mixture is then heated for one hour longer then
i~ poured onto crushed ice. The solid formed is collected by
filtration, washed with water and air dried overnight. The
material is then dried at 65C. to afford 82.0 g. of 6-(p-
-fluorophenyl)-3~2H)-pyridazinone as crystals, m.p. 265-
-268C.
The entire amount of the above compound i3 combined
with 500 ml. of pho3phorus oxychloride and i8 heated on a
steam bath for S hours. The reaction mixture i5 cooled and
the exce~s phosphoru~ oxychloride i8 removed using a rotary
~0 evaporator, then one liter of ice-water i~ added with stirring.
The resulting solid i~ filtered, wa~hed with water and air
dried overnight. The solid is taken up in 2 liters of chloro-
form, treated with activated charcoal and filtered through
diatomaceou3 earth. The chloroform filtrate is concentrated
~5 to a low volume, the precipitate formed i~ collected by fil-
tration and wa~hed with chloroform, then air dried to afford
3-chloro-6-(~-fluorophenyl)pyridazine a~ pinkish crystals.
A 2.5 g. portion of the above compound i~ mixed with
1.46 g. of formylhydrazine and 40 ml. of butyl alcohol. The
mixture is heated to reflux and i8 refluxed overnight. The
mixture is cooled in an ice bath and the precipitated product
1~ collected by filtration, is washed with butyl alcohol and
is dried overnighk. The dried material i~ recrystallized
- 25 -
.
' , ' : ~'::
from methyl alcohol to give the product of the example as
crystal3, m.p. 197-198C.
Example 9
Preparation of ~ 1,2,4-tria~olo[4,3 b]pyridazin-6-yl)benzo-
S nitrile
An 86.3 g. ~ample of 6~ bromophenyl)-4,5-dihydro-
-3~2H~-pyridazinone (prepared a~ in United States Patent No.
3,689,65~, ~xample 5) is di~solved in 500 ml. of glacial ace-
tic acid by heating to 80C. with continuous stirring. A
~olution of 60 g. of bromina in 80 ml. of acetic acid i~ added
dropwise at 75~-80C~ over a one hour period. A solid is
separated near the end of the addi~ion. The reaction mixture
i~ heated with ~tirring on ~he steam bath for half an hour
more, then is poured into 3 liter of cracked ice-wat~r. The
white solid formed is collected by filtration and i~ air dried.
The product i~ then recrystallized from ethyl alcohol to af-
ford 6~ bromophenyl)-3(2H)-pyr:Ldazinone~
A mixture of 19.20 g. of the product above and
9.10 g. of cuprou~ cyanide in 70 ml. of d1methylformamide is
~tirred at reflux temperature for 5 1/2 hours. A ~olid i~
precipitated during thi3 time. The hot mixture i9 poured in-
to a ~olution of 46 ml. of ethylenediamine in 230 ml. of
water. The mixture i~ ~tirred at ic~-bath temperature for
30 minute~, the precipitate i8 collected by filtration and
wa~hed with water until the wa~hing9 are colorle~ to afford
p-~1,6~dlhydro-6-oxo-3-pyridazinyl)ben~onitrile a~ a yellow
~olid.
A ~tirred ~olution of 3.42 g. of the preceding ma-
terial in 25 ml. of pho~phorus oxychloride i~ heated at re-
flux temperature ~or 3 hours. Mo~t of ~he exce~ pho~phoru~
o~ychloride i8 removed under reduced pres~ure then cracked
ice-water i~ added to the concen~rate which i8 ~tirred~ The
~olid 1~ coll~cted by filtration and a~ter air-dr~ing i9
_ ~6 -
.
:
recry-talli~ed from dimethylformamide-water to give ~-(6-
-chloro 3-pyridazinyl)benzonitrile as cry~tals, m.p. 236
-238C.
A mixture of 1.00 g. of the above product, 0.84 g.
of formylhydrazine and 25 ml. of n-butyl alcohol is stirred
at reflux temperature for 17 hours and 45 minutes. The 501-
vent i5 removed under reduced pre~sure and the residue is
triturated with ethyl alcohol. The mixture i8 filtered and
the solid i~ recry~tallized from dimethylformamide wa~er to
afford ~-(1,2,4-triazolo[~,3-b~pyridazin-6-yl)benzonitrile
a~ an orange solid, m.p. 272~274C.
Example 10
Preparation of m-(7-methyl-1,2,4-triazolo[4,3-b]pyridazin-6-
-yl)benzonitrlle
A 15 g. portion of m-~1,4,5,6-tetrahydro-~-methyl-
-6-oxo-3-pyridazinyl)benzonitrile [Journal of Medicinal Chem-
istry 17, 281 (1974)] i~ ~uspendled in 75 ml. of ~lacial acetic
acid with ~tirring at steam bath temperature. Then 3.75 ml.
of bromine in 2S ml. of acetic acid i~ added dropwi3e over a
15 minute period. The reaction mixture i~ heated on a ~team
bath for an additional 30 minutes then is poured onto crushed
ice. The resulting ~olid is collected by filtration, copiously~
wa~hed with water and dried to afford m-(1,6-dihydro-4 methyl-
-6-oxo-3-pyridazinyl)benzonitrile as a cream colored solid.
A 10.0 g. portion of the above material and 100 ml.
of phosphorus oxychloride iB heated on a ~eam bath for 3
hours. The excess phosphorus oxychloride is decompo~ed by
the 810w addition o~ tha reaction mixture to cold water with
stirring. The resulting solid ls filtered and the filter cake
i9 copiou~ly wa~hed with water. The product is air dried to
afford m-(6-chloro-4-methyl-3-pyridazinyl)benzonitrile as a
cream colored 301id.
mixture of 3 0 ~. of the above compound, lo 57 g~
' '
-
of formylhydrazine and 100 ml. of butyl alcohol i9 stirred at
reflux for 18 hours. The reaction mixture is cooled in ah
ice bath and filtered to collect the solid formed. The prod-
uct of the example is then recrystallized fro~ methyl alcohol
S to afford a cream colored solid, m.p. 214-216C.
Example 11
Preparation of 3-propyl-6-(a,a,a-trifluoro-m-tolyl)-1,2,4-
-triazolo[4t3~b]pyridazine
A 112 g. portion of ~-toluenesulfonic acid i~ dis-
solved in 500 ml. of tetrahydrofuran with ~tirring. Then
106 g. of morpholine is added portionwise with ~tirring~ A
95.63 g. portion of m-krifluoromethylbenzaldehyde is added
and the reaction mixture is stirred at reflux for 2 hours.
The reaction mixture is cooled and a solution of 42.2 g. of
potassium cyanide in 75 ml. of water i~ added. The mixture
i~ then allowed to stir at reflux overnight. The reaction mix-
ture i~ concentra~ed free of ~olvent and the concentrate i~
partitioned between water and chloroform. The organic layer
i~ washed with saturated sodium bis~lfite, dried over magne-
sium sulfate, treated with activated charcoal and filtered.
The filtrate i~ concentrated in vacuo to afford a- (a,a,~-tri-
fluoro-m-tolyl)-4-morpholineacetoni~rile as a dark yellow oil.
A 67~0 g. portion of ~he oil above i5 di~solved in t~-o liters
; of tetrahydrofuran with stirring at room temperature. Stir-
ring is continued while eight 10 ml. portion~ of ethyl acry-
late and nine S ml. portion~ of a 30% ~olution of potassium
hydroxide in ethyl alcohol are added to the reaction mixture
over a 5 hour ~eriod. This reaction i~ ~lightly exothermic.
The reaction mi~ture i8 allowed to stir at room temperature
overnight. The mixture i8 treated with activated charcoal
and filtered. The filtrate i~ concentrated free of ~olvent
then i9 ~tripped several time~ with toluene. The concentrate
i~ stirred ~ith diethyl ether ~nd filtered to remove insolu-
_ ~8 ~
ble~. The filtrate ic concentr~ted to a yellow oil then is
chromatographed on a 75 cm. x 8 cm. glass column containing
silica gel with chloroform as ~he ~olvent. The chromato-
graphed material ic stripped of chloroform to afford 47.0 g.
of ethyl ~-cyano-r-(~,~,a-trifluoro-m-tolyl)-4-morpholinebuty-
rate a~ a yellow oil. The entire amount of the preceding pro-
duct i~ combined with two liter~ of ethyl alcohol and 7.3 ml.
of hydrazine hydrate. The ~ixture i~ ~tirred at reflux for
18 hours, then i~ concentrated free of ~olvent to afford a
yellow oil which is ~tirred with ~etroleum ether to yield
14.55 g. of 4,5-dihydro-6-~a,a,a-trifluoro-m-tolyl)-3(2H)-
-pyridazinone as a white solid. The total amount of the pro-
duct above is dissolved in 225 ml. of glacial acetic acid at
ambient temperature, then 3.33 ml. of bromine i~ dissolved in
; 15 25 ml. of acetic acid and 2.5 ml. of thi~ 301ution i8 added
to the starting material above at room temperature. The re-
action mixture is warmed on a ~team bath for half an hour
while the remaining bromine-acetic acid solution i~ add~d
dropwise. Following complete di3coloration, the reaction mix-
ture is heated on a ~team bath for half an hour, and is con-
centrated free of solvent. The ~olid concentrate is washed
with water, filtered and air dried to afford 6-(a,a,a-tri-
fluoro-m-tolyl?-3(2H)-pyridazinone as a cream colored solid.
A 12.55 g. portion of the above product and 200 ml.
of phosphorus oxychloride is heated on a ~t~am bath for 18
hours~ The reaction mixture i9 concentrated free o~ excess
phosphorus oxychloride and the concentrate i~ triturated with
cold water. The resulting ~olid i8 filtered and the filter
cake iq washed with water. The matarial iB air dried to af-
ford 3-chloro-6-(~,a,~-trifluoro-m-tolyl)pyridazine a~ a cream
colored ~olid.
A mixture of 6.0 q. of the preceding product, 4.74 g.
of butyric acid hydrazide and 75 ml. of ~utyl alcohol is al-
_ ~9 _
.2
lowed to stir at reflux for 48 hour3. The reaction mixture
is concentrated free of solvent and the concentrate is taken
up in ethyl alcohol, treated with activa~ed charcoal and fil-
tered. The filtrate i~ concentrated to a ~mall residue,
cooled in an ice bath and the resulting solid is filtered to
afford the product of the example as a cream colored ~olid.
Thi~ material i8 recrystallized from ethyl alcohol and dried
_ vacuo to afford crystal~, mOp. 118-120C.
Example 12
Preparation of 3'-t7-methyl-1,2,4-triazolo~4,3-b]pyridazin-
-6-y~)acetanilide
A 1.5 g. portion of 6-(m-aminophenyl)-7-me~hyl-1,2,4-
-triazolo[4,3-b]pyridazine (prepared as in Example 6) is dis-
solved in 30 ml. of pyridine at room temperature. To the
~olution i~ added 6.0 ml. of acetic anhydride and the reaction
mixture i3 heated on a steam bath for one hour. The reaction
mixture i~ cooled in an ice bath and i~ filtered. The filter
cake i~ wa~hed with petroleum ether and is drie~ to afford
the product of the example as cream colored crystals, m.p.
298-301C.
Example 13
Preparation o~ 6-(~-bromophenyl)-7-methyl-1,2,4-triazolo-
.
[4,3-b]pyridazine
A 10.0 g. portion of 6-(~-bromophenyl)-5-methyl-
-3(2H)-pyridazinone ~Journal of Medicinal Chemi~try 17, ~81
(1974)1 and 100 ml. of phosphoru3 oxychloride i~ heated at
~team bath temperature for 3 hours. The mixture i~ added drop-
wi~e to cold water while stirring The re~ulting soli~ i8
filtered and washed with water to aford 3-(E~bromophenyl)-
-6-chloro-4-methylpyridazine as a grey ~olid.
A mixture of l.S g. of the above compound, 0.64 g.
of formylhydrazine and 25 ml. of butyl alcohol i~ ~tirred at
reflux for 18 hours. The reaction mixture i~ cooled in an
- 30 -
ice bath, filtered and the solid is recrystallized from methyl
alcohol to afford the product of the example as a yellow
solid, m.p. 219-222C.
E~ample 14
S Preparation of ~-(7-methyl-1,2,4-triazolo[4,3-b]pyridazin-
-6-yl~thiobenzamide
A 2.1 g. portion of ~-(7-methyl-1,2,4-triazolol4,3-
-~]pyridazin-6~yl)benzonitrile tprePared as in Example 1) i~
partially dis~olved in a solvent mixture of 50 ml. of pyridine
plus 5.0 ml. of triethylamine. Hydrogen sulfide ga~ is bub-
bled into the reaction mixture over a 3 hour period during
which time the color of the reaction mix~ure changes from
yellow to green. A solid begin~ to form in the reaction mix-
ture approximately 15 minutes after the addition of the hy-
drogen sulfide gas is begun. The mixture is then filtered ;
and the yellow solid i~ washed with petroleum ether to afford
the product of the example a~ a bright yellow ~olid, m.p.
268-272C.
Example 15
Preparation of 6-(3-bromo-~-methoxyphenyl~-1,2,4-triazolo-
[4,3-b]p~ridazine
A ~u~pen~ion of 100 g. of 6-(3 bromo-4-methoxyphen-
yl)-3(2H)-pyridazinone [J. Heterocyclic Chem. 11, 775 (1974)]
in 150 ml. of pho~phorus oxychlorida is refluxed until a clear
solution is obtained (approximately 5 hour~). The ~olution
is cooled and exces3 phosphoru~ oxychloride i8 removed under
~acuum to give a brown solid which i8 triturated with ice
water. ~he solid is collected by filtration and i~ recry~-
tallized to afford 3-(3-bromo-4-methoxyphenyl)-6-chloropyri-
dazine.
; A mixture of 5.28 g. of the preceding compound,
75 ml. of butyl alcohol and 2.88 g. of formylhydrazine is
heated to refl~x and 1~ refluxed overnight. The reaction
~S :
.
.
'` - '. . ' - ~ ,. :, ~
mixture is cooled to room temperature and the product is col-
lected by filtrationO This material i~ then recrystallized
~rom methyl alcohol to give the product of the example as
cry~tal~, m.p~ 226~228C.
Example 16
Preparation of 6-(~-chlorophenyl)-3-methyl-1,2,4-triazolo-
.
4~
A 47.5 g~ portion of 6~ chlorophenyl)-4,5-dihydro-
-3(2H)-pyridazinone (prepared as in Example 1 of Vnited
State~ Patent No. 3,689,652) is dis-~olved in 250 ml. of gla-
cial acetic acid at 65-70C with stirring. Then a solution
of 14 ml. (42 g.) of bromine liquid in 50 ml. of acetic acid
i~ added portionwise during a 20 minute period. The reaction
mixture is stirred at 65C. for 3 hours and is cooled to 4C.
The precipitate is collected and wa~he~ with 100 ml. of ethyl
acetate. The ~olid is suspended in 500 ml. of water, 25 ml~
of concentrated ammonium hydroxide i6 added and the mixture
is ~tirred at room temperature overnight. The precipitate is
collected, washed with 500 ml. of water and dri~d at 60C. to
afford 6~ chlorophenyl)-3(2H)-pyridaæinone.
A mixture of 34.5 g. of the preceding material and
150 ml. of pho~phoru~ oxychloride is refluxed for 4 hoursO
The reaction mixture is cooled and poured into 2 kg. of ice.
After standing for 2 hour~ with occa~ional stirring, the pre-
cipitate i9 collected and wa~hed with water. The ~olid i~
di~solved in S00 m~. of boiling benzene, clarified with acti-
va~ed charcoal and filtered. The filtrate i8 cooled to room
temperature and the solid i~ collected, washed with a ~mall
amount of benzene ~nd air dried. This material is recrystal-
lized from ethyl alcohol after treatmsnt with actlvated char-
coal. The product i~ collected, washed with ethyl alcohol
followed by ether to afford 3-chloro-6-(~-chlorophenyl~pyri~
dazine, m.p. 209-211C.
- 3~ -
A mixture of 10.0 g. of the product above, 6.6 g.
of hydraæine hydrate and 150 ml. of bu~yl alcohol is re~luxed
overnight. The reaction mixture is cooled, filtered and the
~olid washed with butyl alcohol and with water. The butyl
alcohol filtrate above i~ concentrated on a rotating evapora-
tor and additional crystalline product is ob~ained which is
washed with butyl alcohol and with water. The combined mater-
ial afford~ 6-(~-chlorophenyl)-3-hydrazinopyridazine, m.p.
156-160C.
A mixture of 6.6 g. of the above material (prepared
in the manner described), 140 ml. of ~-dioxane and 4.64 g. of
aiisopropylethylamine is warmed until solution occurs. The
solution is then cooled to near room temperature and 2.66 g.
of acetyl chloride is added. The reaction mixture is then
cooled in an ice bath and allowed to stir overnight. The`
solvent is then removed und~r vacuum and ethyl alcohol is
added to the residue. The flask i~ warmed and a solid is
precipitated. This material is removed by filtration and the
ethanol is further concentrated to afford the product of the
~ 20 example as cry~tals, m.p. 208-210C.
: Example 17
Preparation of 6~ chlorophenyl)-8-methyl-1,2,4-triazolo-
[4~3-blpyridazine
To a solution of 114 g. of methylsuccinic anhydride
in 400 ml. of chlorobenzene is added carefully 270 g. of alu-
minum chloride. The mixture i~ heated to 65C. for 1 1/2
hourg, i8 cooled, quenched with ice and concentrated hydro-
chloric acid and extracted with benzene. The benzene layer
i~ extrac~ed with aqueous ~odium bicarbonate. After adjust~
ing the pll of the bicarbonate solution to 6.3, concentrated
hydrochloric acid 1~ added slowly over a perio~ of several
hours with stirring. At pH 5.7, 78 g. of white crystals are
filtered off. Recrystallization of this material fxom eth-
- ~3 -
anol-water affords 3~ chloroben~oyl)-2~methylpropionic acid
as white cry~tals. A mixture of 35.50 g. of the preceding
compound, 85 ml. of hydrazine hydrate and 400 ml. of ethyl
alcohol is allowed to stir at reflux for 18 hours. The re-
action mixture is concentrated to about 75% of the original
volume, cooled in an ice bath and filtered to yield 26.62 g.
of 6-(~-chlorophenyl)-4,5-dihydro-4-methyl-3(2H)-pyridazinone
a~ a yellow ~olid. An additional 4.7 g. of product i~ ob-
tained from the filtrate above.
The combined product above (31.32 g.) i~ dissolved
in 250 ml. of glacial acetic acid at room temperature with
stirring~ An 8.2 ml. portion of liquid bromine is dis301ved
in 50 ml. of glacial acetic acid and 25~ of this ~olution is
added to the reaction mixture. The temperature of the reac-
tion mixture is increased until all the coloration due to
bromine i~ gone. The remaining bromine ~olution is added
with warming over a ~0 minute period. The reaction mixture
i~ warmed on the steam bath for an additional 1/2 hour and
i~ diluted with ice water. The resulting ~olid is filtered,
washed with water and air dried to afford 6-(~ chlorophenyl)-
-4-methyl-3(2H)-pyridazinone as a cream colored solid.
A 15.0 g. portion of the preceding compound and 200
ml. of phosphorus oxychloride i8 heated on a ~team bath for
18 hours. The reaction mixture is concentrated free of sol-
~5 vent and the concentrate i~ stirred with cold water. The pre-
cipitate i9 filtered and the solid i8 wa~hed with water to
afford 3-chloro-6~ chlorophenyl)-4-methylpyridazine as a
pink solid.
~ 2.0 g. portion of the compound above i~ mixed
with 1.08 g. of formylhydrazine and 60 ml. of butyl alcohol.
The mixture is refluxad for ~8 hour~. The reac~ion mixture
- i8 cooled in an ice bath and the re~ultlng ~olid i~ filtered,
washed with petroleum ether and air dried ~o afford a tan
- 311 -
:
solid. The product of the example is recrystallized from
methyl alcohol after treatment with activated charcoal to
afford white crystals, m.p. 230-233C.
Example 18
Preparation of 3-methyl-6-(a,~,a-trifluoro-m-tolyl)-1,2,4-
-triazolo14,3-b]pyridazine
A 6.0 g. portion of 3-chloro-6-(a,a,a-trifluoro-m-
-tolyl)pyridazine (prepared as in Example 11), 3.44 g. of
acetylhydrazine and 75 ml. of n-butyl alcohol i8 refluxed for
48 hours. The ~olvent is removed undar vacuum and the resi-
due dissolved in ethyl alcohol and treated with acti~ated
carbon. The filtrate is concentrated, chilled and filtered
to give an oran~e solid. Recrystallization from methyl alco- -
hol afford~ the product of the example as crystal~, m.p.
193-194C
Example l9
Preparation of 6-~p-chlorophenyl)-1,2,4-triaæolo[4,3-b]pyrida-
zine
A mixture of 9.0 g. of 3-chloro-6~ chlorophenyl)-
pyridazine (prepared as in Example 16), 5.1 g. of formylhydra-
zine and 60 ml. of butyl alcohol is heated at reflux t~mpera-
; ture for 40 hours. The reaction mixture is cooled, filtered
and the solid washed with petroleum ether and with water. The
material i~ then heated with 125 ml. of ethanol and the insolu-
ble material is collected by filtration. The filtrate i3
cooled and the precipitate is collected and combined with the
insoluble material collected above. The combined solids are
recry~tallized from 130 ml. of ethyl alcohol to provide the
product of the example as crystals, m.p. 216-218C.
; 30 Example 20
Preparation of 6-(a,~ t a-trifluoro m-tolyl)-1,2,4-triazolo-
[4j3-b]pyridazine
mixture of 6.0 g. of 3-chloro-6-(a,a,a-trifluoro-
- 35 -
-m-tolyl)pyridazine (prepared as in Example 11) 9 2.78 g. of
formylhydrazine and 75 ml. of butyl alcohol is allowed to ~ir
at reflux temperature for 48 hours. The reac~ion mix~ure is
concentrated free o solvent and the residue i8 di~olved in
ethyl alcohol, treated with activated charcoal and filt0red.
The filtrate i~ cooled in an ice bath and the cream colored
solid i~ collected. The ~olid is heated with diethyl ether
and the mixture i~ filtered. The ~olid i8 recry~tallized from
ethyl acetate to afford the product of the example as cream
colored crystals, m.p. 140-143C.
Example Zl
Preparation of 6-(~-chlorophenyl)~3-ethyl-1,2,4-triazolo-
[4 t 3-b]pyridazine
A mixture of 9.0 g. of 3-chloro-6~ chlorophenyl)-
pyridazin~ ~prepared as in Example 16), 7.4 g. of propionic
acid hydrazide and 60 ml. of butyl alcohol is ~irred at re-
flux temperature for 48 hours. I'he mixture i~ chilled, fil-
tered and the ~olid i8 washed with petroleum ether and with
water. The material i3 recrystallized from 50 ml. of ethyl
alcohol to afford the product of the example as crystals, m.p.
197-199C.
Example 22
Preparation of 6-(~-fluorophenyl3-3-methyl-1,2,4-triazolo-
[4,3-b]pyridazine
A mixture of 6.25 g. of 3-chloro-6-(~-fluorophenyl)-
pyridazine (prepared as in Example 8), 4.65 g. of acetylhy-
drazine and 50 ml. of butyl alcohol is refluxed until a clear
solution re~ults. The reac~:ion mixture i8 cooled, filtered,
and the ~olid precipitate washed with hexane and with water.
The ~olid i8 recrystallized from 50 ml. of ethyl alcohol ~o
give the product of the example as crystals, m.p. 227-229C.
- 36 -
\
Example 23
preparation of 3-methyl-6-(m-nitrophenyl)-1 d 2,4-triazolo-
[4,3-b]pyridazine
A mixture of 9.9 g. of 6-(m-nitrophenyl)-4,5-dihy-
dro-3-pyridazone [J. Med. Chem. 17, 273 (1974)] and 80 ml. of
glacial acetic acid i8 stirred and heated on the steam bath
and a ~olution of 2.41 ml. of bromine in lo ml. of glacial
acetic acid i~ added dropwi~e over a period of 30 minutes.
Heating and ~tirring i~ continued for 45 minutes longer and
the reac~ion mixture is poured onto cru~hed ice. The crys-
talline product is filtered and washed with water. The yield
of 6-(m-nitrophenyl)-3-pyridazone, m.p. 275C., i9 nearly
quantitative.
A mixture of 6 g. of the above product and 35 ml.
of phosphoru~ oxychloride i5 heated on a steam bath for 4 hour~
and concentrated to remove the exce~ POC13. The residue is
poured into ice water and the in~oluble solid is filter~d,
wa~hed with water and air dried. The product is dissolved
in chloroform, treated with activated carbon and clarified.
~he chloroform solution i~ concentrated to obtain 4.0 g. of
3-chloro-6-(m-nitrophenyl)pyridazine, m.p. 206-208C.
A mixture of 3.0 gO of the preceding compound, 2.0 g.
I of acetylhydrazine and 30 ml. of butanol is heated at reflux
temperature for 72 hours and cooled. The precipitate is fil-
tered, washed with hexane, with water, and air dried. The
product i~ boiled with 100 ml. of 9S~ ethyl alcohol and fil-
tered. ~he insoluble material, m.p. 241-243C, i8 3-methyl-
-6-(m-nitrophenyl)-1,2,4-triazolo[4,3-b]pyridazins.
Example 24
Preparation of 6-(m-nitrophenyl)-1,2,4-triazolo[4,3-b]pyrida-
ine
The above compound, m.p. 231~-233C., is obtained
when formylhydrazine i8 sub~ituted for acetylhydrazine in the
- 37 -
-
procedure of Example 23.
Ex~3~le 25
_._
Preparation of 6-(m-aminophenyl)-3-methyl-1,2,4-triazolo-
[4,3-b]pyr _azine
A mixture of 5.1 g. of 3-methyl-6-(m-nitrophenyl)-
-1,2,4-triazolo[4,3-b~pyridazin~ (prepared as in Example 23),
60 ml. of trifluoroacetic acid and 0.9 g. of 10% palladium
catalyst on carbon i8 shaken in a Parr hydrogenator under
about 35 pound~ of hydrogen pre~ ure un~il hydrogen uptake i8
completeO The cataly~t i~ filtered off and the reaction mix-
ture is concentrated. The re~idue i~ dis301ved in water and
adju~ted to p~l 5 by addition of 5N NaOH. Th~ in~oluble ma
terial i~ Eiltered off and wa~h~d with water to obtain 6-(m~
-aminophenyl)-3-methyl-1,2,4-tria~olo[4,3-b]pyridazine, m.p.
193C.
Example 26
Preparation of 6-(m-aminophenyl)-1,2,4-triazolo~4,3-b]pyrida-
zine
The compound of the exalmple, mOp. 225C., i~ obtainPd
when 6-~m-nitrophenyl~-1,2,4-triazolot4,3-b]pyridazine ~pre-
pared as in Example 24) i8 reduced by the pro~edure o~ Exam-
ple 25.
Example 27
Preparation of 6-(m-acetamidophenyl)-1,204-triazolo[4,3-b]-
.... _ _ _ _ .. . . .. . . . . ...
~ridazine
A mixture of 1.0 g. of 6-(m-aminophenyl)-1,2,4-
-triazolol4,3-b]pyridazine (prepared as in Example 26) and
4 ml. of acetic anhydride i8 left at room temperature for 2
hour~ and then i8 triturated with ether and ~ilterQd. The
insoluble ma~erial i9 r~crystallized from ethyl alcohol to
; afford yellow crystal~ of 6-~m= ace~amidophenyl)-1,2,4-~ria~
~ zolo[4,3-b]pyridazine, m.p. 248~-250C.
- 38
, . .
Example 28
Preparation of 6-(m-acetamidophenyl)-3-methyl-1,2,4-triazolo-
14,3-b]~yxidaæine
The compound above is obtained when 6~(m-amino-
phenyl)-3-methyl-1,2,4-triazolo[4,3-b]pyridazine (prepared as
in Example 25) and ace~ic anhydride are reacted as described
in Example 27.
Example 29
Preparation of 3-methyl-6~ tert-butylphenyl)-1,2,4-triazoLo-
[4,3-b]pyridazine
A mixture of 16.5 g. of 3-~-tert-butylbenzoyl pro-
pionic acid [Journal Organic Chem. Soc. 19, 802 (1954)] and
8.25 ml. of hydrazine hydrate is di~solved in 140 ml. of abso-
lute ethyl alcohol. ~he clear solution i~ stirred under re-
flux for 4 hour~ and chilled overnight. The product is col-
; lected, wa~hed with ethyl alcohol and dried in vacuo to yield
- 13.1 g. of 6-(~-tert butylphenyl)-4,5-dihydro-3(2H)-pyridazi-
; - none as a white solid.
; - An 8.00 ~. portion of the preceding material in
80 ml. of gl~cial acetic acid is ~tirred while th~ dropwise
addition of a solution of 5.82 g. of bromine in 20 ml. of gla-
; cial acetic acid is begun. The reaction mixture is heated to
about 100C. and decolorization occur~. The bromin~/acetic
; acid solution is added a~ rapidly as decolorization occurs and
i8 completed in about 15 minute~. The mixture is stirred for
one hour at 100C~, then i9 poured into 150 ml. of ice~ The
white solid formed is collected by filtration, then is dis~
solved in 400 ml. of acetone. The acetone ~olution i~ dried
over magnesium ~ulfate and is concentrated while diluting with
hexane. Crystallization from about 100 ml. of acetone/hexane
affords 4.82 g. of 6~ ter~butylph~nyl)-3~2~)-pyridazinone
a~ a light yellow solid.
A mixture of 22.8 g. of the above compound (~repared
_ 39 _
.
.
.
.. . - ' ~ ~.
. ., : : - . :
in the manner described) and 115 ml. of phosphorus oxychlo-
ride is warmed on a steam bath until a clear solution results.
This solution is heated for 5 hours, then is concentrated in
vacuo. The residue i~ treated with ice water and the result-
ing ~olid i8 collected and dried in vacuo to yield 22.0 g. of
3~ tert-butylphenyl)-6-chloropyridazine as an off-white
solid.
A mixture of 5.0 g. of 3~ t~rt-butylphenyl)-6-
-chloropyridazine, 3.13 g. of acetylhydrazlde and 50 ml. of
n-bu~anol i~ refluxed for 48 hours. The mix~ure i3 concen-
trated under vacuum and the residue ~tirred with 100 ml. of
water and 100 ml. of ether. The mix~ure is filtered to give
3.0 g. of tan ~olid, m.p. 144-146C. Recrystallization from
acetone/hexane gives the product a5 pale yellow crystals,
m.pO 142~145C.
Example 30
Preparation of 6-(~~tert-butylphenyl)-1 t 2,4-triazolo[4,3-b]-
pyridazine
A mixture of 5.0 g. of 3-~-tert-butylphenyl)-6-
chloropyridazine, 2.54 g. of formylhydrazide and 50 ml. of n-
-butyl alcohol is stirred under reflux for 48 hours. The mix-
ture i~ chilled and filtered. ~he solid i8 wa~hed with petro-
leum ether and water and dried in vacuo to yield 0.80 g. of
product. The filtrate i~ concentrated in vacuo below 80C. to
afford additional product which i8 ~tirred with 150 ml. of
water and 150 ml. of diethyl ether, collected by filtration
and drled in vacuo to yield 3.0 g. of an orange ~olid. Re-
crystallization from ethyl alcohol g$ve~ the pro~uct of the
exampl~ as off-white cry~tal~, m.p. 270-27SC.
- 40
Example 31
Preparation of_50 m~. Tabl~ts
Per Tablet Per 10,000 Tablets
0.050 gm. 3-methyl 6-(m-acet-
amidophenyl~-1,2,4-
-triazolo[4,3-b]-
pyridazine 500 gm.
0.080 gm. Lactose 800 gm.
O.010 gm. Corn Starch (for mix)100 gm.
0.008 gm. Corn Starch (for pa~te)75 gm.
O.I48 gm. 1~7~ gm.
0.002 gm. Magnesium Stearate (1%)15 gm.
~ gm. I~ gm
The 3-methyl-6 (m-acetamidophenyl)-1,2,4-triazolo-
[4,3-b]nyridazine, lactose and corn starch ~for mix) are
blended together. The corn ~tarch (for paste) i~ ~uspe~ded
in 600 ml. of water and heated with ~tirring to form a paste.
This paste is then used to granulate the mixed powders. Addi-
tional wnter is used if necessary. The wet granules are
passed through a No. 8 hand ~creen and dried at 120~F. The
dry granules are then pa3sed through a No. 16 ~creen. The
mixture i~ lubricated with 1~ magne~ium -~tearate and com-
pressed into tablet~ in a suitab:Le tableting machine.
ZO Example 32
- Prepara~ion of Oral Su~pen~ion
Ingredient Amount
3-ethyl-6-(~-carbamoylphenyl)-
~1,2,4-triazolo~4,3-b]pyrida-
, zine 500 mg.
Sorbitol solution (70% N.F.) 40 ml.
Sodium benzoate 150 mg.
Saccharin 10 mg.
Red dye 10 mg.
Cherry flavor 50 mg.
Distilled water q~ to100 ml.
The sorbitol solution i~ added to 40 ml. of di~-
tilled water and the 3-ethyl-6-(~-carbamoylphenyl)-1,2,4-
-triazolol4,3-b]pyridazine is suspended therein. The ~accha-
rin, ~odium ben~oate, flavor and dye are added and dis~olved.
The volume i8 adju3ted to 100 ml. with distilled water. Each
ml. of ~yrup contains 5 mg. 3-ethyl-6~ carbamoylphenyl~-
. .
.. :
q~
-1,2,4-triazolo[4,3-b]pyridazine.
Example 33
Preparation of Parenteral Solution
In a solution of 700 ml. of propylene glycol and
200 ml. of water for injection i~ Ruspended 20.0 grams of
3,7-dimethyl-6~ aminophenyl)-1,2,4-triazo1Ot4,3-b]pyridazine
monohydrochloride with ~tirring. After ~uspen3ion i8 complete,
the pH i~ adju~ted to 5.5 with hydrochloric acid and the vol-
ume i~ made up to 1000 ml, with water for injection. The for-
mulation i~ sterilized~ filled into 5O0 ml, ampoules each
containing 2,0 ml, (representing 40 mg~ of drug) and sealed
under nitrogen.
Example 34
Preparation of 6-(~-chlorophenyl)-3,8-dimethyl-1,2,4-triazolo-
[4,3-b]pyridazine
i .
A mixture of 1~0 g. of 3-chloro-6-~-chlorophenyl)-
- -4-methylpyridazine, 0~62 g, of acetic acid hydrazide and
10 ml. of n-butanol i8 refluxed for 48 hours. The solvent i~
removed and the residue di~olvad in dichloromethane and fil-
tered through magnesol. The ~olid from the filtrate i8 re-
cry~tallized from dichloromethane-hexane to give 0.6 g, of
olid, m,p. 209-212~C. Recrystallization from dichloromethane-
-hexane gives the product of the example as light pink colored
crystals, m.p. 215-217C,
Example 35
; Preparation of 6-(~ trifluoro-e~_olyl)-1,2,4-triazolo-
[4,3-b~pyr~d~ i~e
A solution o 76.0 g, of p-toluenesulfonic acid in
400 ml, o~ tetrahydrofuran i8 cooled in an ice bath while
69,5 g, of morpholine i~ aaded~ The cooling bath i~ removed
and upon reaching ambient temperature 65,0 g. ~-tri~luoro-
methyl benzaldehyde i8 added followed by heating at reflux
temperature for 2 hours. The reaction mixture i3 cooled in
ice bath and a solution of 32,6 g. of pota~sium cyanide in
55 ml. of water added followed by heating at reflux tempera-
ture for 18 hours. The solvent is removed and the residue is
partitioned between chloroform and water~ The organic layex
is washed with water, saturated sodium bisulfite and saturated
sodium chloride solution, dried and evaporated to yield
~-~a~ trifluoro-p-tolyl)-4 morpholineacetonitrile as a
tan solid, m.p. 89-90C.
- A 301ution of 52.3 g. of ~-(a,~,~-trifluoro-~-tolyl)-
-4-morpholineacetonitrile in 500 ml~ of dry tetrahydrofuran
is stirred at ambient temperature while 1 ml. portions of 30
potassium hydroxide in ethanol and 25 ml. portions of ethyl
acrylate is added every half hour until a total of 5 ml. of
the base and 150 ml. of ethyl acrylate is added. After the
addition, the mixture i~ stirred at ambient temperature for
48 hours. Following filtration9 the filtrate i concentrated,
dissolved in methylene chloride, pasaed through magnesol and
recrystallized from methylene chloride/hexane to a~ford ethyl
Y-cyano-y(~a~a-trifluoro-~-tolyl)-4-morpholinebutyrate as
cream colored crystals, m.pO 96-97C.
A-solution of 38.~ g. of the preceding compound,
900 g. o~ hydrazine hydrate and 600 ml. of ethanol is re1uxed
for 24 hours. The solution is treated with activated char-
coal, filtered and the filtrate concentrated. The residue
is crystallized from methylene chloride/hexane to give 6
-(~,a,~-trifluoro-~-tolyl)-4,5-dihydro-3~2H)-pyridazinone as
cream colored crystals, m.p. 177-178C.
A solution of 14.5 g. of the preceding compound and
10.4 g. of bromine in 150 ml. of acetic acid i8 heated ~lowly
on a steam bath until complete discoloration occura. Heating
i8 continued for an additional 30 minutes followed by pouring
onto crushed ice. The re~ulting solid is filtered, wa~hed
with water to give 6-(~ trifluoro-~-tolyl)-3(2H)-pyrida-
zinone as off-white crystala, mOp. 191-193C.
- l~3 -
A mixture of 11.0 g. of the preceding compound and
150 ml. of phosphorus oxychloride is heated on a steam bath
for 5 hours. The solution is concentrated free of solvent
and the rssidue is wa~hed with cold water to yield 3-chloro-
-6-(a,,~-trifluoro ~-tolyl)pyridazine as a white solid,
m.p. 186-188C.
A mixture of 4.50 g. of 3-chloro-6-(a,~,a-trifluoro-
~-tolyl)pyridazine, 2.09 g. of formylhydrazine and 100 ml. of
n-butanol is stirred and refluxed for 3 days. The solvent
-
0 i8 removed and the residue dis~olved in methylene chloride;
pa~sed through magne~ol and the solid from the filtrate re-
crystallized from methylene chloride/hexane to afford the
product as white crystals, m.p. 160-161C.
Example 36
Preparation of 3-methyl-6-(a,a,~-trifluoro-~-tolyl)-1,2,4-
-triazolo[4,3-b]-pyridazine
A mixture of 4.50 g. of 3-chloro-6-(a,a,~-trifluoro-
-~-tolyl)pyridazine, 2.58 g. of acethydrazide and 100 ml. of
n-butanol is heated at reflux temperature for 3 day~. The
solvent is removed and the re~idue dissolved in methylene
chloride, pa~sed through magnesol and the ~olid from the fil-
trate recrystallized from methylene chloride/hexane to afford
the product as tan cryQtals, m.p. 199-201C.
.~' .
s~
Example 37
Preparation of a-(m-chlorophenyl)-4-morpholineacetonitrile
To a cold solution of 76 g. of ~-toluenesulfonic
acid in 500 ml. of tetrachydrofuran i~ added 87 g. of morpho-
line and 50.6 g. of m-chlorobenzaldehyde. The mixture is
refluxed for 2.5 hrs. and 100 ml. of tetrahydrofuran dis-
tilled off the mixture is cooled, and a ~olution of 28~6 g. of
KCN in 100 ml. of wat~r i~ addedO The mixture i8 refluxed
for 5 hrs. and concentrated to drynes~ under vacuum. The
re~idue is dissolved in methylene chloride and the ~olution
washed with water, odium bisulfite solution/ saturated NaCL
301ution and dried (Na2S04~. The solution is passed through
a short column of hydrou~ magne~ium silicate. The eluent is
refluxed while hexane i5 added until crystals separated.
Cooling and filtering gives 78.0 g. of crystals, m.p. 72-73C.
Example 38
Preparation o 3-(m-chloro~enzoyl)propionitrile
To a solution of 23.6 g. of a-(m-chlorophenyl)-4
-morpholineacetonitrile in 100 ml. of tetrahydrofuran is
added 120 drop~ of a 30~ solution of KOH in methanol. To
the mixture is added 4.1 ml. of acrylonitrile (temperature
rose to 45C.). After stirring 1 hr., the mixture is con-
centrated to dryness under vacuum. The resideu is dissolved
in methylene chloride and passed through a short column of
hydrous magnesium silicateO The eluent i~ concentrated under
vacuum to give 36.6 g. of a yellow oil. The oil is heated
(steam bath~ with a mixture of 150 ml. of acetic acid and 10
ml. of water for 1 hr. The ~olvent is removed under vacuum
and the residue treated with water. The mixture is filtered
to give 18.8 g. of crystals, m.p. 49-51~C.
- Example 39
3-(m-chloroben~oyl)-2-methylpropionitrile
To a solution of 11.8 g. of a-(m-chlorophenyl3-4-
-- 115 -
1-, .
7~
-morpholineace~onitrile in 50 ml. of tetrahydrofuran is
added 60 drops of a 30% solution of KOH in methanol. To the
solution is added 4.62 ml. of methacrylonitrile (temperature
rose to 42C.). After stirring for 1 hr., the mixture is
concentrated to dryness and the residue dis~olved in me~hylene
chloride. The solution is passed through a ~hort column of
hydrous magne~ium silicate and the eluent concentrated to
give 15.5 g. of a yellow oil. The oil i8 heated (steam bath)
with a mixture of 75 ml of acetic acid and 5 ml. of water
for 1 hr. and the solvent removed under vaccuum. Addition
of water to the residue gives 11.2 g. of crystals, m.p. 72-
-75C. Recrystallization from methylene chloride-hexane
giveQ 8.95 g. of crystals, m.p. 79.5-80.5C.
Example 40
Preparation of 3-(m-chlorobenzoyl)-2-methylpr~ionic
A mixture of 7.90 g. of 3-(m-chlorobenzoyl)-2-
- -methylpropionitrile and 75 ml. of concentrated hydrochloric
acid is refluxed for 1 hr. Cooling give~ 8.5 g. of crystal~,
m.p. 102-105C. The crystalQ are dissolved in 50 ml. of lN
NaOH, the mixture is filtered and the filtrate acidified
with lN Hcl. Filtration gives 8.15 gO of crystals, m~p. 103-
-105C.
~ Exampl~ 41
Preparation of 6-(m-chlorophenyl)4,5-dihydro-4-methyl-3(2H)-
-pyridazinone
A mixture of 7.11 g. of 3 (m-chlorobenzoyl)-2-
-methylpropionic acid, 50 ml. of ethanol and 3.0 ml. of hydra-
zine hydrate i8 refluxed for 2 hr~. Cooling and filtering
gives crystals, ~m.pr 150-151C.) which are recrystallized
from ethanol to give 5.72 g. of cry~tals, m.p. 152-153.
Pre~aration of 3-~-chlorobenzoyl ? propionic Acid
A mixture of 8.1 g. of 3-(m-chlorobenzoyl)propioni-
trile and 80 ml. of cone Hcl is refluxed for 7 hrs. Cooling
, . .
p~
gives an oil which crystalli2ed to give 8.8 g. of crystals,
m.p. 105-107C. The crystals are dissolved in lN NaOH and
the mixture filtered. The filtrate is audified with lN HCl
to give 8.7 g. of crystals m.p. 103-105C.
Example 43
Preparation of 6-(m-chlorophenyl~-4-methyl-3~2H)pyridazinone
A solution of 4.66 g. of 6~m-chlorophenyl)-4,5-
-dihydro-4-methyl)-3~2H)pyrida~inone in 60 ml of glacial
acetic acid iB heated on a steam bath and a one-~uarter
portion of a solution of 4.01 g. of bromine in 5 mlO of
acetic acid added. After the bromine color disappeared,
the remainder of the bromine solution is added gradually.
The mixture is heated (steam bath) for 0.5 hr. and poured
onto ice. Filtration gives crystals (m.p. 243.5-245C.)
which are recrystallized from ethanol to give 4.0 g of
crystals, 244-~45C.
Example 44
Preparation of 6-(m~chlorophenyl~-4,5-dihydro-2(2H)pyridazinone
A mixture of 7.70 g. of 3(m-chlorobenzoyl)-propionic
acid, 50 ml. of ethanol and 3.0 ml. of hydrazine hydrate i~
refluxed for 2 hrs. The mixture ia cooled, filtered and the
crystals (6.30 g. m.p. 146-147C.) recrystallized from ethanol
to give 5.50 g. of crystals, m.p. 150-lS1C.
Example 45
Preparation of 6-(m-chlorophenyl)-3(2H)-pyridazinone
A mixture of 4.45 g. of 6-(m-chlorophenyl)-4,5-
-dehydro-3(2~ pyrida~inone and 50 ml. of glacial acetic i~
heated on a steam bath. A one-quarter portion of a ~olution
of 4.01 g. of bromine in 15 mlO of glacial acetic acid is
added. When the bromine color di~appeared, the remainder of
the bromine solution i~ addsd. The mixture i8 heated on a
- ~team bath for an addi~ional 0O5 hr. and the mixture poured
onto ice The mixture is filtered to give 3.30 g. of crystals.
- l~7 -
. .
. . .
~' , . . ~ .
m.p. 214-216C~
Example 46
Preparation of 3-chloro-6-(m-chlorophenyl)-4-methylpyridazine
~ mixture of 25 ml. of pho3phorus oxychloride and
3.0 g. of 6-(m-chlorophenyl)-4-methyl-3(2H)-pyridazinone is
refluxed for 6 hrs. The mixture is concentrated to dryne~s
under vacuum and water added to the re~idue. Filtration
gives 3.28 g. of crystals, m.p. 138-140C. Recrystallized
from ethanol gives 2080 g. of crystals, mOp. 138-141C.
Ex~
Preparation of 3-chloro-6-(m-chlorophenyl)pyridazine
A mixture of 25 ml. of phosphorus oxychloride and
3.0 g. of 6-(m-chlorophenyl)-3(2H)-pyridazinoic is refluxed
for 6 hr. The mixture is concentrated under vacuum and water
added to the residue. Filtration gives 3.30 g. of crystals,
m.p. 155-157 C. Recry~tallization from e~hanol gives 2.75 g
of crystals, m.p. 157-158C.
Preparation of 6-(m-chlorophenyl)-8-methyl-1,2,4-triazolo-
_
-[4,3-b]pyridazine
A mixture of 2.0 g. of 3-chloro-6-(m-chlorophenyl)-
-4-methylpyridazine, 50 ml. of n-butanol and 1.08 g. of
formyLhydrazine i~ refluxed for 18 hr~. The mixture is con-
centrated to dryness under vacuum and the residue dis~olved
in methylene chloride. The solution is passed through a
short column of hydrous magne~ium ~ilicate. The eluent is
- refluxed while hexane is added gradually until crystals sepa-
rated Cooling and filtering gives 1.20 g. of cry tal30 m.p.
173-176C. The crystal3 in methylene chloride are pa~ed
through a ~hort column of hydrous magne~ium silicate and the
eluent concentrated with the additlon of hexane to give 0.83
g. of crystal~, m.p. 181-182C.
3 _
:
Example 49
Preparation of 6-(m-chlorophenyl)-3 methyl-1,2,4-triazolo-
_
-[4,3-b]pyridazine
A mixture of 2.0 g. of 3-chloro-6-(m-chlorophenyl)-
pyridazine, 50 ml. of n-butanol and 1.32 g. of acetylhydrazine
is refluxed for 18 hr~. The mixture i8 concentrated to dry-
ne~s under vacuum and ~he re~idue dis olved in methylene
chloride. The ~olution is pas~ed through a ~hort column of
hydrou~ magnesium silica~. The eluent iB refluxed while
hexane i8 gradually added until crystal~ ~eparated. Cooling
and filtering gives 1.50 g. of crystals, m.p. 171-172.5C.
Example 50
Preparation of 6-(m-chlorophenyl)-3,8-dimethyl-1,2,4-triazolo-
-[4,3-b]pyridazine
A mixture of 7017 g. of 3-chloro-6-(m-chlorophenyl)-
-4-methylpyridazine, 100 ml. of n-butanol and 6.96 g. of
acetylhydrazine i~ refluxed overnight. The mixture is coated
and filtered to give solid. The ~olid i8 dissolved in
methylene chlorids and the solution pa~sed through a short
column of hydrous magnesium silicateO The eluent i~ refluxed
while hexane is gradually added until crystals separated.
Cooling and filtering gives 3.30 g. of cry~tals, m.p. 193.5-
-195.5C.
Exam~le 51
Preparation of 3-(m-chlorophenyl)-6-hydrazinopyridazine
A mixture of 6.85 g of 3-chloro-6-(m-chlorophenyl)-
pyridazine, 100 ml. of _ butanol and 3.05 g. of hydrazine
hydrate iB rafluxed overnight. The solvent i~ removed under
vacuum to give a semi-solid. The solld i~ dis~olved in a
minimum of hot nitromethane. Cooling gives 3.5 g. of
amorphou~ ~olid.
_ l~g _
' , . ' , ' ' " '
~ J~ ~
Example 52
Preparation of 6~ fluorophenyl)-1,2,4-triazolo-[4,3-b]-
_
pyridazine
As in Example 35, the following reactions are car-
ried out. _-Fluorobenzaldehyde is reacted with p-toluene-
sulfonic acid, morphaline and KCN to give ~-(o-fluorophenyl)-
-4-morpholineacetonitrile as a yellow oil. The product
y (o-fluorophenyl)-4-morpholineacetonitrile is reacted with
ethyl acrylate to give ethyl y-cyano-y-(o fluorophenyl)-4-
-morpholenebutyrate as an oil. A solution of the preceding
compound and hydrazine hydrate in ethanol i5 refluxed to give
6-(o-fluorophenyl)-4,5 dihydro-3(2H)-pyridazinone as crystals,
m.p. 119-121C. The preceding compound i8 heated with bromine
in acetic acid to give 6-(o-fluorophenyl)-3(2H)pyridazinone as
- 15 cry~tal~ (from CH2C12-hexane), m.p. 173-175C.
A mixture of the preceding compound and phosphorus
oxychloride is refluxed on a steam bath to give 3-chloro-6-
-(o-fluorophenyl)pyridazine as crystals, m.p. 95-96C.
A mixture of 5.0 g. of 3-chloro-6-(o-fluorophenyl)-
pyridazine and 2.88 g. of formylhydrazine in 75 ml. n-butanol
i~ refluxed for 48 hrs. and worked up a-~ in Example 35 to
give 1.1 g. of product as cream colored crystal~, m.p. 161-
-163 .
Example 53
Preparation of 3-methyl-6-(o-fluorophenyl)-1,2,4-triazolo-
-~4,3~eyridazine
As in Example 36, a mixture of 2.5 g. of 3-chloro-
-6-(o fluorophenyl)-pyridazine and 1.76 g. of acetylhydrazine
in 50 ml~ of n-hutanol i~ refluxed for 48 hr. to give 2.0 g.
of product as off-white cry~tal~, m.p. 147-149C.
Example 54
Preparation of 6-tm-fluorophenyl)-1,2,4-triazolo-[4,3-b]~ ;
__ _ _ _ .
~y__dazine
- 50 -
: .
:
' ' ~ .. ' . ~ .
7~
A~ in Example 35, the following reaction3 are
carried out. m-Fluorobenzaldehyde is reac~ed with ~-toluene-
sulfonic acid, morpholine and KCN to give a-(m-fluorophenyl)-
-4-morpholineacetonitrile as cry~tal~ (from CH2C12-hexane)
m.p. 74-75C.
The preceding compound iR reacted with ethyl
acryla~e to give ethyl y cyano-y-(m-fluorophenyl)-4-morpho~
linebutyrate as crystal~ (from C~2C12-Hexane), m.p. 88-90C.
A solution of the preceding compound and hydrazine
hydrate in ethanol i~ refluxed to give 6-(m-fluorophenyl)-4,5-
-dehydro-3 (2H)pyridazinone aR crys~als (from CH2C12-hexane),
m.p. 132-134C.
The preceding compound i~ heated with bromine in
acetic acid to give 6-~m-fluorophenyl)-3(2H)pyridazinone a~
crystals (from CH2C12-hexane), m.p. 207-209C.
- A mixture of the preceding compound and pho~phorus
oxychloride is refluxed to give 3-chloro-6-(m-fluorophenyl)-
pyridazine a~ crystals, m.p. 133--135C.
A mixture of 3.6 g. of ~-chloro-6-(m-fluorophenyl)-
pyridazine ~nd 2.06 g. of formylhydrazine in 50 ml. of n-bu~
tanol i~ refluxed for 48 hr. and worked up as in ~xample 35
to give the product ~8 crystal~, m.p. 159-161C.
Exam~le 55
Preparation of 3-methyl-6-(m-fluorophenyl)-1,2,4-triazolo-
_
-[4,3-b]pyridazine
As in ExDmple 36, a mixtura of 3.0 g~ of 3-chloro-
-6~ fluorophenyl)pyrid~zine, 2.14 g. o~ aeetylhydrazine
and 50 ml. of n-butanol i9 refluxed 4a hr~. to glve 2.0 g.
of the product a~ cry~tale, m.p. 1~4-186C.
Example 56
Preparation of 6-(o-chlorophenyl)-1,2,4-triazolo-
-~4,3-b]~y~idazine
As in Example 35, tha following reaction3 are
- 51 -
carried out. o-Chlorobenzaldehyde is reacted with ~toluene-
sulfonic acid, morpholine and ~CN to give ~-(_-chlorophenyl)-
-4-morpholineacetonitrile as crystals (from CH2C12-hexane),
m.p. 40-42C.
The preceding compound is reacted with ethyl acrylate
to giva ethyl ~-cyano-y-(_-chlorophenyl)-4-morpholinebutyrate
as an oil.
A solution of the preceding compound and hydrazine
hydrate in ethanol is refluxed to give 6-(o-chlorophenyl)-
-4,5-dihydro-3(2H)pyridazinone as cry~tals, m.p. 114-116C.
The preceding compound i~ heated with bromine in
acetic acid to give 6-(o-chlorophenyl)-3(2H)-pyridazinone
as crystals, m.p. 214-216C.
A mixture of the preceding compound and phosphorus
oxychloride is refluxed to give 3-chloro~6-(o-chlorophenyl)-
pyridazine as crystals, m.p. 145-147C.
A mixture of 5.67 g. oE 3-chloro-6-(o-chlorophenyl)-
pyridazine, 3.03 g. of formylhydrazine in 50 ml. of butanol
i8 refluxed 48 hr~. to give 2.3 g. of product a~ pale yellow
crystal3, m.p. 156-158C.
~ .
Preparation of 3-methyl-6-(o-chlorophenyl)-1,2,4-triazolo-
-l4,3 ~LJ~L id~ne
As in Example 36 r a mixture of 5.5 g. of 3~chloro-
~5 -6-(o-chlorophenyl pyridazine, 3O6 g. of acetylhydrazine in
75 ml. of n-butanol is refluxed for 72 hr~. to give 2.2 g.
of product as off-white crystals, mOp. 146-148C.
Example 58
Preparation of 4-methyl-6-(a,a,o-trlfluoro~m-tolyl)-
3 -4,5-dihydro-3(2H)-pyrid~zinone
To a solution of 60.0 gO of a-(a,a,a-trifluoro~m-
-tolyl)-4-morpholine~cetonitrile in 200 ml. of tetrahydrofuran
i~ added S ml. of a ~olution of 30~ po~a~ium hydroxide in
- 52 -
.
7~
methanol. To the mixture is added 22,0 ml. of methacryloni-
trile and the mixture is stirred overnight. The mixture is
concentrated to dryness under vacuum and the re~idue dis-
~olved in chloroform. The ~olution i9 passed through a
column of hydrou~ magnesium ~ilica~e. The eluent i8 con-
centrated to a yellow oil which i~ crystallized from ether-
hexane to give 47 g. of cream colored crystals, m.p. 88-
-90C. The preceding compound (107 g.) i8 heated on a steam
bath with a mixture of 600 ml. of acetic acid and 75 ml. of
water for 18 hr. The ~olvent is removed to give an oil.
A mixture of the oil in S00 ml. of 6N Hcl is refluxed for
24 hrs. The mixture is cooled and extracted with chloroform.
The chloroform layer is washed with water and sa~urate NaCl
solution and passed through a column of hydrous magnesium
silicate. The solvent is removed from the eluent and the
re~idue crystallized from ether-hexane to give 29.4 g. 2-
-methyl-3-(m~trifluoromethylbenzoyl)propionic acid as light
pink crystals, m.p. 90-93C.
A mixture of the prececling compound (25.4 g.) and
5.0 ml. of hydrazine hydrate in 200 ml. of ethanol is refluxed
for 18 hr. The mixture is cooled and filtered to give 21.8 g.
of product as cream colored crystals, m.p., 188-190C. A
sample is recrystallized from CHC13-hexane to give off white
cry3tals, m~p. 191-193C.
Example 59
Preparation of 8-methyl-6-(a,a,a-trifluoro-m-tolyl~-
-- -- .
-1~2~4-triazolo-14,3-b]pyridazlnè
To a solution of 4-methyl-6-(~,~,a-trifluoro-m-
-tolyl)-4,5-dihydro-3(2H~pyridazinone(20.5 g.) in 200 ml. of
acetic acid is added portionwi~e 14.4 g. of bromine in 25 ml.
of acetic acid. The mixture i9 heated for 0.5 hr. and the 901-
vent removed under vacuum. To the residue i~ added ice and
water and the mixture ~s filtered to give 20~4 g. of 8-methyl-
- 53 -
- .
-6-(~,a,~-trifluoro-m-tolyl)-3(2H)pyridazinone a~ cream
colored crystals, m.p. 234~237C.
The preceding compound (19~4 g.) and 200 ml~ of
pho~phorus oxychloride is heated on a ~team ba~h for 18 hr.
The mixture is concentrated to dryness under vacuum and to
the residue is added ice and water. The mixture is filtered
and the ~olid recry3tallized from CHC13-hexane to give 18.0 g.
of 3-chloro 4-methyl-6~ ,a-trifluoro-m-tolyl)pyridazine
as cream colored crystal~, m.p. 123-126~C.
A mixture of 8.0 g. of the preceding compound~ 3.S2 g~
of formylhydrazine and 125 ml. of n-butanol i~ refluxed for
48 hr. and concentrated to dryness under vacuum. THe residue
in CHC13 is pas~ed through a column of hydrous magne~ium
silicate, the eluent is concentrated and the residue crystal-
lized from CH2C12-hexane to give the product as crystals, m.p.
3C.
Example 60
Preparation of 3,8-dimethyl~6~ -trifluoro-m-tolyl)-1,2,4-
.
-triazolo[4,3-b]pyridazine
As in Example 36, a mixture of 8.0 g. of 3-chloro-
-4-methyl-6-(a,~,a-trifluoro-_-tolyl)pyridazine, 4.34 gO
of acetylhydrazine in 125 ml. of n-butanol i~ refluxed for
; 48 hr. to give 3.9 g. of product as crystals, m.p. 196-198C.
Exam~le 61
Preparation of 7-methyl-6-ta,~,a-trifluoro-m-tolyl)-1,2,4-
-triazolo[4,3-b]pyridazine
~o a ~olution of ~ ,a,a-tri1uoro-m~tolyl)-4-
-morpholineacetonitrile in 100 ml. o tetrahydrofuran i~
added 1.0 ml. of 30~ XOH-ethanol solution. To the mixture
i8 added 2.56 g. of crotononitrile and the mixture i~ stired
at room temperature for 18 hrs~ The mixture i~ concentrated
to dryne~s under vacuum and the residue is di~301ved in
chloroform. The solution i5 pa~sed through a col~nn of hydrou~
- 5l~ -
magnesium silicate. The eluent is concentrated to an oil
(17.3 g.) which is crystallized from hexane and recrystal-
lized from CHC13-hexane to give 3-methyl-2-morpholino-2-
-(a a,a-trifluoro-m-tolyl)glutaronitrile a~ crystals, m~p.
115-118C.
A mixture of the preceding compound (39 g.) in
500 ml. of 75% acetic acid is refluxed for 48 hr. and the
solvent removed under vacuum. The residue is dissolved in
CH2C12 and the solution washed with wa~er, saturated sodium
bicarbonate and saturated NaCl solution. The organic layer
dried (MgSO4) and passed through a column of hydrous magnesium
silicate. The eluent ls concentrated ~o give 27.4 g. of 3
-(m-trifluoromethylbenzoyl)butyronitrile as a yellow oil.
A mixture of the preceding compound (26.4 g.) and
500 ml. of 6N HCl is refluxed for 18 hr. The mixture is
cooled and extracted with dichloromethane. The organic
layer is extracted with ~aturatecl NaHCO3 solution. The
basic aqueou~ extract is acidifi~d with 6N HCl and extracted
w_th ether. The ether layer is washed with ~aturated NaCl
solution, dried (MgS04) and concentrated to give 24.3 g. of
3-~m-trifluoromethylbenzoyl)-butyric acid a~ a colorless oil.
. _
A mixture of the preceding compound (24 L3 g~
5.0 ml. of hydrazine hydrate and 200 ml. of ethanol i~ re-
fluxed for 18 hr. and the solvent removed under vacuum. The
residue is disqolved in dichloromethane and the solution
passed through a column of hydrou3 magnesium ~ilicate. The
eluent i~ concentrated to give 20~7 g. of 5-methyl-6-(a,a,a-
-trifluoro-m-tolyl)-4,5-dihydro-3(2H)pyridazinone as white
crystals, m.p. 132-134C. Recry~tallization from CH2C12-hexane
gives white crystal~, m.p. 142-144C.
The preceding compound i 8 heated with bromine in
acetic acid to give 5-methyl-6-(~,a,~-trifluoro-m-tolyl)
-3(2~)pyridazinone a~ white crystals, m.p. 224 227C.
- 55 -
Example 62
Preparation of 3,7-dimethyl-5-( a, a, ~-trifluoro~m-tolyl)-
_
-1,2,4-tria~olol4,3-b]pyridazine
As in Example 36~ a mixture of 8O0 g. of 3-chloro-
5-methyl-6-(~ trifluoro-m-tolyl)pyridazine and 4.34 g.
of acetylhydrazine in 125 ml. of _-butanol is refluxed for
48 hr. to give 6.2 g~ of cream colored crystal~, m.p. 185-
-187C.
Example 63
Preparation of 6-(m-tolyl)-1,2,4-triazolo[4,3-b~pyridazine
As in Example 35, the following reaction~ are
carried out. m-Tolualdehyde is reacted with ~toluenesulfonic
acid, morpholine and KCN to givs ~-(m-tolyl)-4-morpholine-
acetonitrile as crystals, m.p~ 59-60C.
~he preceding compound is reacted with ethyl acrylate
to give ethyl y-cyano-y-(m-tolyl)-4-morpholinebutyrate as an
oil.
A solution of the preceding compound and hydrazine
hydrate in ethanol is refluxed to give 6-(m-tolyl)-4,5-dihydro-
-3(2H)pyridazinone a~ white cry3tals, 130-132C.
The preceding compound is heated with bromine in
acetic acid to give 6-(m-tolyl)-3(2H)pyridazinone as white
crystals, m.p. 202-205C.
~ mixture of the preceding compound and phosphorus
oxychloride is refluxed to give 3-chloro-6-(m-tolyl)-pyrida-
zine as off-white crystals, m.p. 112-113C.
A mixture of 6.0 g. of 3-chloro-6-tm-tolyl)pyrida-
zine and 3~52 g~ of formylhydrazine in 100 ml. of n-butanol
i~ refluxed for 48 hrs. and worked up as in Example 35 to
give 2.0 g. of white crystal~ (from CHC13-hexane), m.p. 164
-166C.
- 5~ -
. . . : . .
', '
E~am~le ~4
Preparation of 3-methyl-6-(m-tolyl)-1,2,4-triazolo~4,3-b]-
pyridazine
As in Example 36, a mixture of 6.0 g, of 3~chloro-
-6-(m-tolyl)pyridazine and 4.34 g. of acetylhydrazine in 100
ml. of n-butanol is refluxed for 48 hr. to give 2.0 g. of
cream colored crystal~, m.p. 160-162C.
Example 65
Prepar~tion of 3-propyl-6-(~,~, a - tr i fluoro-~-tolyl)-1,2,4-
-triazolo-[4,3-b]p~ridazine
A mixture of 5.0 g. of 3-chloro-6-(a,a,~-trifluoro-
; -p-tolyl)pyridazinet 3.94 g. of butyric acid hydrazide and
100 ml. of n-butanol is refluxed for 48 hr. The ~olvent is
removed under vacuum and the residue dissolved in chloroform.
The solution is passed through a column of hydrous magnesium
~ilicate and the eluent concentrated to give 3.2 g. of product
- Recry~tallization from CHC13-hexane gives crystals, m.p. 173-
-175C.
Example 66
Prepara~ion of 3-ethyl-6-(,~,~-trifluoro-m-tolyl)-1,2,4-
~triaæolo[4,3-b]pyridazine
A mixture of 5.0 g. of 3-chloro-6-(~,a,a-trifluoro-
- -m-tolyl)pyridazine, 3.40 g. of propionic acid hydraæide and
100 ml. of n-butanol is refluxed for 48 hr. The ~olvent is
removed under vacuum and the residue dis~olved in chloroform.
The solution i3 pa~sed through a column of hydrous magnesium
silicate and the eluent concentrated to give 3.0 g. of cry~tals
(from CHC13-hexane), m.p. 183-185C.
Example 67
Preparation of 3-ethyl-6~ -trifluoro-~-tolyl)-1,2,4-
-triazolo[4_3-b]pyridazlne
As in Example 6~, 5.0 g. of 3-chloro-6~
-trifluvro-~-tolyl)pyridazine and 3.40 gO of propionic acid
57
hydrazide in 100 ml. of butanol i~ refluxed for 48 hr. to give
3.1 g. of white crystals (from CHC13~hexane), m.p~ 194-196C.
Example 68
Preparation of 6-(4-chloro~ trifluoro-m tolyl)-1,2,4-
-triazol 4,3-b]pyridazine
According to the method in "Organic Syntheses",
5-amino-2-chlorobenzo~rifluoride i~ converted to 4-chloro-
3-(trifluoromethyl)benzaldehyde. As in Example 35, the
following reactions are carried out. 4-Chloro-3-(trifluoro-
methyl)benzaldehyde (13.9 g.), 14.27 gO of ~-toluenesulfonic
- acid, 13 01 g. of morpholine and 4.88 g. of pota~sium cyanide
i~ reacted to give ~-[4-chloro-3-(trifluoromethyl)phenyl]-
4-morpholineacetonitrile as white crystals, m.p. 73-74C.
This compound (14.0 g.) is reacted with ethyl acrylate to
give ethyl Y-cyano~r-~4-chloro-3-(trifluoromethyl)phenyl]-
4-morpholinebutyrate a6 a yellow oil (16~5 g.). This compound
(16~5 g) is reacted with 2.11 g. of hydrazine in 100 ml.
of ethanol to give 6-[4-chloro-3-(trifluoromethyl)phenyl]-
4,5-dihydro-3(2H)-p~riaazinone (4.2 g.) as white crystals,
m.p. 195-198C. This intermediate is heated with bromine in
acetic acid to give 6-[4-chloro-3-(trifluoromethyl)phenyl]-
-3(2H)-pyridazinone a~ white crystals, m.p. 249-251C.
A mixture of thi~ compound (5 g.) and 60 ml. of phosphoric
oxychloride i~ refluxed 18 hours to give 3-chloro-6-[4-chloro-
-3-(trifluoromethyl)phenyl]pyridazine a~ cream colored cry~tal~,
m.p. 145-147C. A mixture of 2.2 g. of the preceding com-
pound, 0.9 g. of formylhydrazine, and 50 ml. of n-butanol i8
refluxed for 48 hour~ to give 2.1 g. of product, m.p. 211-
-214C. Recry~tallization from _-propanol give~ cream colored
crystals, m.p. 217-218C.
58
' . ' ' ~ , ", " '
. ~ :
Example 69
Preparation of 3-methyl-6-(4-chloro~ trifluoro-m-tolyl)-
-1,2,4-triazolo[4,3-b]~yridazine
As in Example 36, a mixture of 2.2 g. of 3-chloro-
-6-[4-chloro-3-(trifluoromethyl)phenyl]pyridazine and 1.11 g.
of acetylhydrazine in 50 ml. of butanol is refluxed for 48
hours to give the product as crystal~, mOp. 267-269C.
Example ?
Preparation of 6-(3,4-dichlorophenyl~-1, 2 r 4-triazolo[4,3-b]-
~ridazine
As in Example 35, the following reactions were
- carried out. 3,4-Dichlorobenzaldehyde (106.3 g.) is reacte~
with 124 g. of ~-toluenesulfonic acid, 122 g. of morpholine,
and 45 g. of potassium cyanide in 5Q0 ml. of ~etrahydrofuran
to give 136.9 g. of ~-(3,4-dichlorophenyl)-4 morpholineaceto-
nitrile as cream colored cry~tals, m.p~ 69-71C. This
compound (136.9 g.) i reacted wlth 50 ml. of ethyl acrylate
in 600 mlO of tetrahydrofuran to give 132.6 g. of a tan oil.
Thi~ oil (132.6 g.) and 36 ml. of hydrazine hydrate in S00
ml. of ethanol i5 refluxed to give 63.5 g. of 6-(3,4-dichloro- -
phenyl)-4,5-dihydro-3(2H)-pyridazinone a~ yellow crystals,
m.p. 168-182C. Thi~ intermediate (63.~5 g.) and 67.5 g.
of ~odium m-nitrobenzenesulfonate and 52.0 g. of sodium
hydroxide in 2 liters of water is hea~ed on a s~eam bath
overnight to give 26.4 g. of 6-~3,4-dichlorophenyl)-3(2H)-
pyridazinone as tan crystals, m.p. 215-218C. The preceding
compound (10 g.) and 100 ml. of pho~phorus oxychloride is
heated on a steam bath to give 8.9 g. of 3-chloro-6-~3,4-
-dichlorophenyl)pyridazine. Column chromatography on silica
gel with chloroform-methanol (95.5) gives 5.5 g. of produc~
as crystal~, m.p. 188-189C.
- 59 -
71
Example 7~
Preparation of 50 m~. Tablets
Per Tablet Per 10,000 Tablets
0.050 gm. 3,7,8-Triethyl-6-
-phenyl-1,2,4 tria-
zolo[4,3-b]pyridazine SOO gm.
0.080 gm. Lactose 800 gm.
O.010 gm. Corn Starch (for mix) 100 ~m~
0.008 gm. Corn Starch ~for pas~e) 75 gm.
~IT~ gm. I~7~ ~m
0.002 gm. Magnesium Stearate (1%) 15 gm.
0.150 gm. I~ gm.
The 3,7,8-triethyl-6-phenyl-1,2,4-triazolol4,3-b]-
pyridazine, lactose and corn starch (for mix) are blended to-
gether. The corn starch (for paste) is suspended in 600 ml.
of water and heated with stirring to form a paste. This paste
is then used to granulate the mixed powders. Additional water
is used if necessary. The wet granules are pas~ed through a
No. 8 hand ~creen and dried at 120F. The dry granules are
then passed through a No. 16 screen. The mixture is lubri-
cated with 1~ magnesium stearate and compressed into tablets
in a suitable tableting machine.
Ex~ple ~
Preparation of Oral ~uspension
In~redient Amount
3,8~Di-n-butyl 6-phenyl-1,2,4-
-triazolol4,3~b]pyridazine500 mg.
Sorbitol solution (70~ N.F.) 40 ml.
Sodium benzoate 150 mg.
Saccharin 10 mg.
Red dye 10 mg.
Ch~rr~ flavor 50 mg.
Distilled water q5 ad 100 ml.
The sorbitol solution i~ added to 40 m}. of dis-
tilled water and the 3,8-di-n-butyl-6-phenyl-1,2,4-triazolo-
[4,3-b]pyridazine is ~uspended there$n. The saccharin, ~o-
dium benzoate, fla~or and dye are added and dissolved~ The
volume i~ adjusted to 100 ml. with distilled water. Each ml.
of syrup contains 5 mg. of 3,8-di n-butyl-6-phenyl-1,2,4-
-triazolol4,3-b]pyridazine.
- 60 -
æ
.
~3
ExamE~e ~
Preparation of Parenteral Solution
In a solution of 700 ml. of propylene glycol and
200 ml. of water for injection is suspended 20.0 grams of
7,8-di-n-propyl-6-phenyl-1,2,4-triazolo[4,3-~]pyridazine mono-
hydrochloride with stirring. A~ter suspension i~ complete,
the pH i~ adju~ted to 5.5 with hydrochloric acid and the vol-
ume i~ made up to 1000 ml. with water for injection. The for-
mulation i~ sterilized, filled into 5.0 ml. ampoule~ each
containing 2.0 ml. (repre~enting 40 mg. of drug) and ~ealed
under nitrogen.
Example 7~
Preparation of 3,7,8-trimethyl-6-p~enyl-lL2,4 tria~olol4,3-b]-
p~ridazine
A 200 g. poxtion of 3-benzoyl-2,3-d1methyl-propionic
acid and 60 g. of hydrazine hydrate are added to one liter
of ethyl alcohol and stirred at reflux for 1~ hours. The re-
action mixture is ~hen cooled in an ice bath and collected
in a conventional manner to afford 4,5-dihydro~4,5-dimethyl-
; 20 -6-phenyl-3~2H)-pyridazinone as a cream colored ~olid. This
product is partially dissolved in 600 ml. of glacial acetic
acid. To this is added, portionwise, a solution of 50 ml. of
bromine in 100 ml. of glacial acetic acid, while warming on
a steam bath (approximately 15~ of the bromine solution is
added to the reaction mixture before warming i~ 3tarted and
about one hour i8 required to complete the addition during
which time quantitie~ of hydrogen bromide gas are given off).
After the addition is completed, the reaction mixture i9
heated on the steam bath for one hour, and then the mixture
i3 poured onto crushed ice. The re~ulting solid i3 vacuum
` fil~ered, wa~hea copiou31y with water, and air dried to give
4,5-dimethyl-6-phenyl-3t2H)-pyridazinone as a cream colored
solid. Thi~ materlal i3 added to 800 ml. of phosphorus oxy-
- 61 -
- chloride and is heated on a steam bath for 5 hours. ~he re-
action mixture is concentrated to remove the excess phosphorus
oxychloride and is then diluted with cold water. The result-
ing solid is vacuum filtered, washed copiously with water,
and air dried to give 3-chloro-4,5-dime~hyl 6-phenylpyridazine
as a pinkish ~olid. A 10 g. por~ion of this product plus 8 g.
of N-acetylhydrazine and 100 ml. of n-bu~yl alcohol is allowed
to stir at reflux for 48 hour~ The reaction mixture i5
cooled in an ice bath and the re~ulting solid is vacuum fil-
~ered, wa~hed first with petroleum ether and then with water,
and is air dried. The solid i5 recrystallized from ethyl al-
cohol after treatment with activated charcoal and is dried
in vacuo to give 3,7,8-trimethyl-6-phenyl-1,2,4-triazolo-
14,3-b]pyridazine a~ a white ~olid.
~ .
IS Example
Preparation of 7-methyl-6-phenyl-l~2~4-triazolo[4~3-b]pyrida
z ine
A 10 g. portion of 6-(~-bromophenyl)-5-methyl-3(2H)-
-pyridazinone [J. Medicinal Cham.~ 17, 281 (1974)] and 100 ml.
20 . of pho~phorus oxychloride are heated at steam bath tempera-
;- ture for 3 hours. The mixture is added dropwi~e to cold water
while stirring. The re~ulting solid is filtered and washed
with water to afford 3-(_-bromophenyl)-6-chloro-4-me~hyl pyri-
dazine as a grey solid. A mixture of 1.5 g. of this compound,
0.64 g. of formylhydrazine and 25 ml. of n-butyl alcohol iB
~tirred at reflux for 18 hours. The reaction mix~ure i~ cooled
in an ice bath, filtered, and the ~olid is recrystallized
from methyl alcohol giving 6-(~-bromophenyl)-7-methyl-1,2,4-
-triazolo~4,3-b]pyridazine.
A mixture of 10 g. of the above material, 30 ml. of
ammoni~m hydroxide, 250 ml. of ethyl alcohol and a catalytic
amount of 10~ palladium on charcoal i8 ~hakan ln a Parr sha-
ker for 18 hours. The uptake of 35 pounds of hydrogen is
- ~2 -
71L2
complete in 2 hours. The reaction mixture i~ then filtered
; to remove the catalyst and the ~iltrate i~ concentrated to a
white solid which is triturated with petroleum ether. The
solid i~ collected by filtration, air dried and recry~tallized
from methanol ethyl acetate to give 7-methyl-S-phenyl-1,2,4-
-triazolo[4,3-b]pyridazine a~ white cry~tal~, m.p. 188-190C.
A Exampl ~
.
Preparation of 3-m~thyl-6-phenyl-1,2,4~triaæolo[4,3-b]pyrida-
zine
The title compound i~ prepared by the method of
Duffin _ al. a~ set forth in Briti3h Patent No. 839,020
is~ued on June 29, 1960. 17
Exam~le ~
Pre~aration of 3,8-dimethy~1-6-ph n~-1c2,4-triazolo[4,3~b]-
pyridazine
The title compound i~ pxepared by ~he me~hod of
- Leclerc & Wermuth a~ ~et forth in Bull. Soc. Chim~ France,
No. 5, 1752 (1971).
Exam~le ~Q
Preparation o~ 7- ~ ropyl-6-phenyl-1,2,4-triazolo[4,_-b]-
pyridazine
The procedure of Example 4 i~ repeated ~ubstituting
equimolecular amounts of 3-~onzoyl-3-iso~ropyl-propionic acid
and N-formylhydrazine for the 3-benzoyl-2,3-dimethyl-prop~onic
acid and N-acetylhydrazine employed in that ~xample. There
is thu~ obtained the title co~ ound in equally good yield.
Exam~le ~
Preparation of 8-isobutyl-6-phenyl-l,Z,4-triazolo[4,3-b]pyri-
dazine
Following the general procedure of Example 4, 3-
-banzoyl-2-isobutyl-propionic aoi~ i~ converted to 3-chloro-
-4-isobutylpyridazine which i8 treated with N-formylhydrazina
to g~ve the tltle compound.
- 63 -
7~L~
Exam~le ~L
Preparation of 3-ethyl-7~methyl-6-phenyl-1~2,4-triazolo~4,3-b]-
p~ri azlne
The general procedure of Example 4 i~ repeated but
replacing the 3-benzoyl-2,3-dimethyl-propionic acid and N-
- -acetylhydrazine employed in that example with 3-benzoyl-3-
-methyl-propionic acid and N-propionylhydrazine.
~/
Example 8~
Preparation of 6-~henyl~1,2,4-triazolo[4,3-b]pvridazine
A 10 g. portion of 3-chloro-6-phenylpyridazine
(Chem. Ab~., 44, 561~i), 6.6 g. of formylhydrazlne and 100 ml.
of n-butanol are refluxed for 48 hours. Ths reaction mixture
i~ cooled in an ice bath. ~he resulting ~olid i8 filterèd,
washed with petroleum ether and water and air dried giving
6-phenyl-1,2,4-triazolo[4,3 b]pyridazine a~ tan crystals,
m.p. 138-139C.
Example ~
- Preparation of 8-me~hyl-6-phenyl-1,2~4-tria2010[4L3-b?E~rida-
zlne
A mixture of 13.2 g. of 4-methyl-6-phenyl-3(2H)-
-pyridazinone and 200 ml. of pho~phorus oxychloride i~ heated
on a steam bath for 18 hour~. The reaction mixture i~ fil-
tered. The filtrat~ i8 concentrated free of excess phosphorus
oxychloride. The residue is 3tirred with ice water and fil-
tered. The ~olid i5 washed with water and air dried giving
3~chloro-4-methyl-6-phenylpyridazine as a cream colored solid.
A mixture of 2.05 g. of tho above product, 1.2 g. of
formylhydrazine and 50 ml. of _-butanol i~ stlrred and re-
fluxed for 48 hour~. The reaction mixture i~ concentrated
free of solvent and the re~idue i8 tirred with diathyl ether.
The mixture i3 filtered giving a cr~am colored ~olid. Thi~
qolid i~ recrystalllzod from methanol aft2r treatment with
activated charcoal. The methanol filtrata i8 allowed to
- ~4 -
7~
evaporate slowly at room temperature resulting in the forma-
tion of white needles along with a dark yellow oil. The oil
is removed and the needle~ are wa~hed with a ~mall amount of
diethyl ether which i~ decanted. The needles are then recrys-
tallized from methanol-diethyl ether-petroleum ether giving
- 8-methyl-6-phenyl-l~2r4-triazolo[4~3-b]pyridazine as white
crystals, m.p. 150-151C.
Exam~le ~
Preparation of 3-n-propyl-6-phenyl-1,2,4-triazolo[4,3-b]pyri-
dazine
A mixture of 10 g. of 3-chloro-6-phenylpyridazine,
11.2 g. of butyric acid hydra~ide and 100 ml. of n-butanol i~
heated at reflux for 40 hour~. The solution is cooled and
the precipitate is iltered and wa~hed with petroleum ether
and watex. The filtra~e is concentrated to an oil which forms
a precipitate upon the addition of petroleum ether. The pre-
cipitate is collected and washed with petroleum ether and
water. The solid~ are combined and recrystalli~ed from 30 ml.
of ethanol giving 3-n-p~opyl-6-phenyl-1,7,4-triaæolo[4,3-b~--
pyridazine as crystals, m.p. 123-125C.
Example ~iY
Preparation of 3-ethyl-6-phenyl-1,2,4-~riazolo~4,3~b]~yrida-
zine
A mixture of 7.6 ~. of 3-chloro-6-phenylpyridazine,
7.4 g. of propionic acid hydrazide and 60 ml. of n-butanol i5
~tirred at reflux temperature for 48 hours. The solu~ion is
cooled in a chilled room, concentrated to remove the solvent
and triturated with water giving cry~tal~. The mixture i~
filtered, wa~hed with petroleum ather and water and dried.
The product i~ recry~tallized from 20 ml. of ethanol giving
3-ethyl-6-phenyl-1,2,4-triazolo[4,3-b]pyridazine, m.p. 133-
135~
- 65 -
~3~
A mixture of the preceding compound and formyl-
hydrazine in n-butanol is refluxed for 24 hr~. to giv~ 6-
-(3,4-dichlorophenyl)-1,2,4-triazolo[4,3-b]pyridazine.
xample ~K
~ Preparation of 3-methyl-6-(3,4-dichlorophenyl)-1,2,4-triazolo
[4 ! 3-b]p~_ida~ine
A mixture of 2.6 g. of 3-chloro-6-(3,4-dichlor~-
phenyl)pyridazine and 1.8 g. of acetic acid hydrazide i8 heated
in 50 ml. of n-but~nol for 24 hr-~. to give the product of the
example.
Example ~
Preparation of 6-[2-chloro-5-(trifluoromethyl)phenyl]triazolo-
[4,3-b]pyridazine
A~ in Example 68, 3-amino-4-chlorobenzotrifluoride
is converted to 2-chloro-5-(trifluoromethyl)benzaldehyde, ~hich
is converted to 3-chloro-6-~2-chloro-5-(trifluoromethyl)phenyl]
pyridazine a~ cream colored cry~als. A mixture of 2.2 g. of
this compound) 0O3 g. of formylhydrazine ~nd 50 ml. of n-
-butanol i~ refluxed for 48 hour~ to give th2 product of the
example.
Example ~ff~
Preparation of_3-methyl-6-[2-chloro-5w(trifluoromethyl)phenyl]-
-1,2,4-triazolo[4~3-b]pyridazine
A~ in Example 36, a mixture of 2.2 g. of 3-chloro-
-6-[2-chloro-5-(trifluoromethyl)phenyl]pyridazine and 1.11 g.
of acetylhydrazine in 50 ml. of n-butanol i8 refluxed for 48
hour~ to glve the product of the example.
Example ~
Preparation of 6-[4 nitro-3-(trifluoromethyl)phenyllo3~2H)-
.
--p~ridazinone
.
A mixture of 2.0 g. of 6 [3-trifluoromethyl)phenyl]-
- -3(2H)-pyridazinone ~nd 10 ml. of ~umlng nitric acid is heated
on a ~team bath for 30 min. The mixture ia poured onto
- 66 -
cru~hed ice, filtered and the ~olid washed with water~ The
yellow solid (2.2 g.) i8 dissolved in 20 ml, of 5N MaOH. The
mixture i8 chilled (ice bath) and ~iltered. The solid is
dis~olved in water the BolUtion acidified with hydrbchloric
acid. The olid i~ filtered and washed with water to give
1.0 gn of cream colored cry~tal~, m.p. 235-238C. Recry~tal-
lization from dimethyl~ormamide-water gave product a~ crys~
m.p. 238-241C.
Example ~ q
10~ Preparation of 6-[4-nitro-3-(trifluorom~thyl)phenyl]-1,2,4-
~ - .
-tria~olo [4,3~b]pyridazine
A mixtur~ of ~.0 g. of 6-[4-nitro-3-(trifluoro-
methyl)phenyl]-3(2H)-pyridazinone and 80 mln of phosphorus
oxychloride is heatad on a ~team bath or 18 hours. The
solvent i~ removed and ice water added to the residue. Fil-
tration give~ 7.2 g. of 3-chloro~6-[4-nitro-3-(trifluoro-
methyl)phenyl]pyridazine as tan cry~tals, m.p. 129 135C.
Recrystallization from dichlorometh~ne-hexane gives cream
colored cry~tal~, m.p. 151-155"C. ~ha preceding compound
i~ reacted with formylhydrazine in refluxing n-butanol for
24 hours to give the product of the example.
Ex~mple 9~
Prèparation o~ 3-methyl-6~[4-nitro-3-(trifluoromethyl)phenyl]-
.
; 25 A mixture of 4.0 g. of 3-chloro-6-[4-nitro-3-~tri--
fluoromethyl)phenyl~pyridazine and 1.95 g. of acetylhydrazine
in 40 ml. of n-butanol i~ refluxed ~or 18 hour~ to glve the
product ~8 cry~t~ls, m.p. 293-295C.
; Ex~mple ~
Preparation of 6-[4-fluoro-3-(trifluoromethyl)ph~nyl] 1,2,4-
-~ri~o1~~ L~
A mixture of 10 g. of 6-[4-nitro~3-(trlfluoromethyl)
- 67 -
phenyl] 3(2H)-pyridazinone in 50 mlO of trifluoroacetic acid
is reduced with hydrogen and palladium on carbon to give
6-[4-amino-3-(~rifluoromethyl)phenyl]-3(2H)-pyridazinone.
The preceding compound i~ converted to 6-[4-fluoro-3-(tri-
fluoromethyl)phenyl]-3(2~)-pyridazinone by the procedure
described in J. Org. Chem., 26, 468 ~1961). The pr~cedlng
compound i~ reacted with pho~phoru~ oxychloride as described
in Example 47 to give 3-chloro-6-[4-fluoro-3-(trifluoromethyl)-
phenyl]pyridazine., which is reacted with formylhydrazine as
de~cribed in Example 48 to give the product of the example.
9~
Example ~$~
Preparation of 3-methyl-[4-fluoro-3-(trifluoromethyl)phenyl]-
-1,2,4-triazolo[4~3-b]pyridazine
A~ de~cribed in Example 36, 3-chloro-6-[4-fluoro-3-
-(trifluoromethyl)phenyl]pyridazine is reacted with acetic
acid hydrazide in n-butanol to give tha product of the
, example.
93
Example ~
Preparation of 3-methyl-~4-chloro-3-(trifluoromethyl)phenyl]-
-1,2L~ ~Lia7wlo[4~3-bl-~vrldazine
According to procedure in J. Org. Chem., 25, 468
(1961), 6-~4-amino-3-(trifluoromethyl)phenylC-3(2H)-pyridazi-
none i~ converted to ~-[3-chloro-S-(trifluoromethyl)phenyl]o
-3(2H)-pyridazinone. The preceding compound i~ reacted with
phosphoru~ oxychloride to give 3-chloro-6-[4-chloro-3-tri-
fluoromethyltphenyl]pyridazlne which i8 r~cted with ~cetic
~cid hydrazide, as in Example 36, to glve the product m.p.
267-~69C.
q~
~ , .
Prep~ration of 3-methyl-6-[4-amino-3-(trifluorom~thyl)phenyl]
A mixture of 5 g. of 3-methyl-6-[3-nitro-5-trifluoro
methyl)phenylJ-1,2,4-triazolo[4,3-b]pyridazine $n 75 ml. of
- 68 -
..
'
~3~
trifluoroacetic acid is reduced with hydrogen and palladium
on carbon catalyst to gi~e the product of the example.
Recrystallization from methanol give~ cream colored cry~tals,
m.p. 240-242C.
5 ~ Example ~
Preparation of 3-methyl-6-(2-chloro-5-methylphenyl)-1,2,4-
_ _ . . . _ _ _ . . ... _ _ . _ _ _ _
-tri~zolo[4,3-b]p~rid~zine
As described in Example 35, 2-chloro-5-methyl-
benzaldehyde i8 reacted with morpholine and potas~ium cyanide
to give y-(2-chloro-5-me~hylphenyl)-4-morpholineacetonitrile.
In a ~imilar manner as de3cribed in Example 35, the preceding
- compound i~ converted to 3-chloro-6-(2-chloro-5-methylphenyl)~
pyridazine which is reacted with acetic acid hydrazide in
refluxing n-butanol for 24 hour~ to give the product of the
example.
'q~
Ex~mple ~
Preparation of 3-ma~hyl-6-(2,3-dichlorophenyl)-1,2,4-triazolo-
. .
[4,3-b]pyrid zine
AB de~cribed in Example 35, 2,3-dichlorobenzalde-
hyde i8 converted to 3-chloro-6-(2,3-dichlorophenyl)pyridazine.
A mixture of thi~ compound and acetic acid hydrazide in n-
-butanol i~ refluxed for 24 hours to give the product o~ the
example.
Y7
; Example ~
Preparation of 6-(2-methyl-5-chlorophenyl)-1,2,4-triazolo-
[4,3-b~pyridazine
A~ de~cribed in Ex~mple 35, 2-methyl-5-chlorobenæalde-
hyde i9 converted to 3-chloro-6-(2-methyl-5--chlorophenyl)-
pyridazine. A mixture of the preceding compound and formyl-
hydr~zlne ln n-butanol i9 refluxed for 24 hour~ to give the
product of the ex~mple~
- 69 -
q~
Examjele ~g~
Preparation of 6-~3-chloro-5-(trifluoromethyl)ph~nyl]-
... . ..
-1,2,4-triazolo[4,3-b]pyridazine
A~ de~cribed in Ex~mple 35, 3-chloxo-5-(trifluoro-
methyl)benzaldehyde 1~ converted to 3-chloro-6--[3-chloro-5-
-~trifluoromethyl)phenyl]pyridAzins, Thi~ compound i~ reacted
with formylhydrazine in refluxing n-bu~anol for 24 hours to
give the product of the exampleO
Exam~le ~
Preparation of 3-methyl-~-[3-chloro-5-(trifluorome~hyl)phenyl]-
-1~2J_-triazolo[4,3-b]pyridazlne
A mixture o~ 3-chloro-6-[3-chloro-5 (trifluoromethyl)-
phenyl]pyridazine and acetlc acid hydrazide in n-butanol i8
refluxed for 24 hour~ to give th~ product of the ex~mple.
'7O
