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Патент USA US3037032

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States Patent 0
3,037,022
Patented May, 29, 1962
1
2
melting at 262—264°, with decomposition. The structure
3 037 022
may be expressed as
N-(DIHYDROXYPYR’IDAZINYDANILINE AND
DERIVATIVES THEREOF
OH
Harman S. Lowrie, Northbrook, Ill., assignor to G. D.
’ Searle & Co., Chicago, 111., a corporation of Delaware
No Drawing. Filed Sept. 7, 1960, Ser. No. 54,377
10 Claims. (Cl. 260-250)
The present invention relates to pyridazine derivatives
of aniline of the formula
10
OH
EXAMPLE 2
OH
N- [4-(3,6-Dihydroxypyridazinyl) ]-4-Methylaniline
Z
i“
N
H
Substitution of 500 parts of p-toluidine for the aniline
of
Example 1 gives, by the procedure therein detailed,
15
N- [4- ( 3,6-dihydroxyp3u'idazinyl) ] ~4-methylaniline, melt
ing at 247-249" with decomposition. The structure may
N
I
OH
be expressed as
wherein Z is hydrogen, alkyl, (alkyDoxy and halogen.
Among the alkyl radicals referred to above, especially 20
lower alkyl radicals are preferred, for examply, methyl,
’
OH
CH;;—
ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl,
tert-butyl, pentyl, isopentyl, tert-pentyl, neopentyl,
_NH I i
hexyl, isohexyl, heptyl, and octyl. Among the halogens
referred to above, especially halogen of atomic weight
less than 80 is preferred.
The compounds to which this invention relates possess
OH
EXAMPLE 3
N- [4- (3 ,6-D ihydroxypyridazinyl ) ]-4-Ethylaniline
Substitution of 500 parts of p-ethylaniline for the aniline
valuable pharmacological properties. In particular, they
possess appetite inhibiting and diuretic activity.
of Example 1 gives, by the procedure therein detailed, N
The compounds of the present invention are con
[4- ( 3,i6-dihydroxypyiidazinyl) ]-4-ethylaniline.
veniently prepared by condensation of a suitably sub
stituted aniline with 4-chloro-3,6-dihydroxy-pyridazine in
the presence of copper powder.
l
+
—NH2
I ~—>
01-
N
I
OH
’
|
]
35
i 1
N
.be expressed as
'
.
onao-
signed.
The following examples describe in detail certain of
the compounds illustrative of the present invention and
methods which have been devised for their manufacture.
. ”/&N
_N_
N
H \/
5
However, the invention is not to be construed as limited
thereby, either in spirit or in scope, since it will be ap
parent to those skilled in the art of organic synthesis
'
OH
40
In the equation Z has the signi?cance hereinbefore as
that many modi?cations, both of materials and of methods,
may be practiced without departing from the purpose
and intent of this disclosure. In the examples hereinafter
detailed, temperatures are given in degrees centigrade,
pressures in pounds per square inch, and relative amounts
of materials in parts by weight, except as otherwise noted.
Substitution of 500 parts of p-anisidine for theraniline
of Example 1 gives, by the procedure therein detailed, N
[4-(3,6 - dihydroxypyridazinyl)]-4-methoxyaniline melt
I
OH
g
ing at 225—230° with decomposition. The structure may
N
H
EXAMPLE 4
N- [4- (3,6-Dihydroxypyridazinyl) ]-4-Meth0xyaniline
on
Z
N
6H
EXAMPLE 5
N- [4-(3 ,6-Dihydroxypyridazinyl ) ]-4-Eth0xyaniline
Substitution of 500 parts of p-phenetidine for the aniline
of Example 1 gives, by the procedure therein detailed,
~
55
EXAMPLE 1
N-[4-(3,6- Dihydroxypyridazinyl? Aniline
_ N-[4-(3,6-dihydroxypyridazinyl)1-4-ethoxyaniline.
EXAMPLE 6
N- [4- (3,6-Dihydroxypyridazinyl) ]-4-Flu0r0aniline
Substitution of 500 parts of p-?uoroanil-ine for the
aniline of Example 1 gives, by the procedure therein de
tailed, N- [4-( 3,6-dihydroxypyridazinyl) 1-4-?uoroaniline,
melting at 272-274" with decomposition. The structure
pyridazine, 500 parts of aniline and one part of copper 60 'may be expressed as
A mixture of 100 parts of 4-chloro-3,6-dihydroxy
powder is heated rapidly to re?ux temperature. Re?ux
is maintained by the heat of reaction for about 10 minutes,
and by heating for an additional 15 minutes. At the
end of this time the reaction mixture is allowed to
cool to room temperature, and then diluted with an equal 65
volume of ether. The mixture thus obtained is extracted
several times with dilute ‘aqueous potassium hydroxide,
and the extracts are back-extracted with ether, and acidi
(EH
F
/\N
_N
1%
H
OH
EXAMPLE 7
?ed with concentrated hydrochloric acid. The resultant
N- [4- (3,6~Dihydroxypyridazinyl) ]-4-Chl0roaniline
solid material is removed by ?ltration, washed with water 70
on the ?lter, and recrystallized from methanol to give
Substitution of 500 parts of p-chloroaniline for the
N-[4-(3,6-dihydroxypyridazinyl)J-aniline, as tan crystals,
aniline of Example 1 gives, by the procedure therein de
3,037,022
4
tailed, N- [4-(3,6-dihydroxypyridazinyl) ] -3-chloroaniline,
tailed, N- [4- ( 3 ,G-dihydroxypyridazinyl) ] -4-chloroaniline,
melting at 259-262”.
melting at 276—278° with decomposition. The structure
EXAMPLE 15
may be expressed as
OH
A
5
Substitution of 500 parts of m-bromoaniline for the
aniline of Example 1 gives, by the procedure therein de
tailed, N- [4-(3,6-dihydroxypyridazinyl) ] -3-bromoani1ine.
ifN
0H
N- [4-(3,6-Dihydroxypyridazinyl) ]-3'Br0moaniline
10
What is claimed is:
1. A compound of the formula
(in-r
EXAMPLE 8
N-[4-(3,6-Dihydroxypyridazinyl) ]-4-Br0m0am'line
N
Substitution of 500 parts of p-bromoaniline for the
aniline of Example 1 gives, by the procedure therein de
N
on
EXAMPLE 9
wherein Z is a member of the class consisting of hydrogen,
N- [4- (3 ,6-Dihydroxypyridazinyl) ] -3-M ethylaniline
lower alkyl, (lower all<yl)oxy and halogen of atomic
weight less than 80.
Substitution of 500 parts of m-toluidine for the aniline
of Example 1 gives, by the procedure therein detailed,
2. N-[4-(3,6-dihydroxypyridazinyl) ]aniline.
3. A compound of the formula
N- [4- ( 3,6-dihydroxypyridazinyl) 1-3 -methylaniline.
EXAMPLE 10
25
N- [4- (3 ,6-Dihydroxypyridazinyl) 1-3-Ethylaniline
Substitution of 500 parts of m»ethylaniline for the
on
(lower alkyl)
EXAMPLE ll
(‘)H
4. N-[4-(3,6-dihydroxypyridazinyl) 1-4-methylaniline.
5. A compound of the formula
OH
(lower alkyl) 0
35
l
EXAMPLE 12
N- [4- (3 ,6-Dihydroxypyridazinyl ) ]-3-Eth0xyani line
Substitution of 500 parts of m-phenetidine for the
aniline of Example 1 gives, by the procedure therein
l
N
H
OH
6. N- [4- ( 3 ,G-dihydroxypyridazinyl) ] -4-methoxyaniline.
7. A compound of the formula
on
l
X
45
N
H
N
H
Substitution of 500 parts of m-?uoroaniline for the
aniline of Example 1 gives, by the procedure therein de
tailed, N- [4-(3,6-dihydroxypyridazinyl) 1-3-?uoroaniline.
N
40
detailed, N - [4-(3,6-dihydroxypyridazinyl)1-3-ethoxy
aniline.
EXAMPLE 13
N- [4- (3 ,6-Dihydroxypyridazinyl ) ] -3-Fluor0aniline
N
V}:
N-[4-(3,6-Dihydroxypyridazinyl) ]-3-Meth0xyaniline
N- [4-( 3,6-dihydroxypyridazinyl) J-B-methoxyaniliue.
t‘
N
30
Substitution of 500 parts of m-anisidine for the aniline
of Example 1 gives, by the procedure therein detailed,
I
ml
aniline of Example 1 gives, by the procedure therein de
tailed, N- [4—(3,6-dihydroxypyridazinyl) ]-3-ethylaniline.
l
H
tailed, N-[4-(3,6-dihydroxypyridazinyl) ]-4-bromoaniline.
N
(511
50 wherein X is halogen of atomic weight less than 80.
EXAMPLE 14
N- [4- (3,6-D ihydroxypyridazinyl ) ]-3-Chl0r0aniline
Substitution of 500 parts of m-chloroaniline for the
aniline of Example 1 gives, by the procedure therein de 55
8. N-[4-(3,6-dihydroxypyridazinyl)]-4-?uoroaniline.
9. N-[4-(3,6-dihydroxypyridazinyl) ]-4-chloroaniline.
l0. N-[4-(3,6-dihydroxypyridazinyl) ]-3-chloroaniline.
No references cited.
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