Note : Les descriptions sont présentées dans la langue officielle dans laquelle elles ont été soumises.
' L~ NE -
This invention relates ~o a new proCess for the
prepara~ion of 2~methylene-quinoxaline-1,4-dioxide
derivatives known to possass bac~ericidal and wei3ht~gain
increasing effects. The compounds prepared accordirlg ~o
~he inv~ntion are encompassed by ~he general formula /I/
,~\~ N y CH ~ A
wherein
A represents a hydroxyl or an am~no group,
or a group of the general formula -NH COORl, wherein R
denotos a Cl 4 alkyl group;
or a group of the general formula -NH-CX-NH2, wherein X
stands for oxygen or sulfur;
or a group o~ the formulal -NH-C/=NH/-NH2;
or a group of the general formula -NH-R2~ wherein R2
represents Cl 6 alkyl, phenyl, benzyl, hydroxyl or hydroxy-
-/C2_4 alkyl/;
or a group of the general formula -NH-C0-R3, wherein R3
stands for a Cl 20 alkyl group, a phonyl group optionally
substituted by one, ~wo or three iden~ical or different
substituent/s/ selected from the group consisting of
A2310-62 ~ ~.
.. . .
~5~7~7~
~ 2 --
hydroxyl, amino, ni~ro, Cl ~ alkyl, Cl 4 alkoxy or halogen;
a piperîdyl, a pyridyl, a furyl, a nitrofuryl, a pyraz1nyl,
a pyrimidyl, a naphthyl, a hydroxynaphthyl, a phenylalkyl,
an 1,2,~-triazinyl, an ~,~ ~diphenyl- ~-hydroxymethyl, a
cyanomethyl a halomethyl or a hydroxymethyl group~
The ~erm "alkyl group" used in the specification and
claims covars straight-chained or branched saturated aliphatic
hydrocarbyl groups, such a5 methyl,ethyl, n-propyl, isopropyl,
n-butyl, sec~-butyl, tert,-butyl, etc. The term "alkoxy group"
refers to groups derived from the alkyl groups mentioned
above, such as methoxy, ethoxy, n-propoxy, isopropoxy, n-
-butoxy, etc, Preferred representatives of the "hydroxy-
-/C2 4 alkyl/" groups are the hydroxyethyl, hydroxypropyl,
hydroxyisopropyl and ~he hydroxybutyl groups. The term
- 15 "halogen" may stand for all the four halogen a~oms, such
as fluorine, chlorine, bromine and iodine. The term "haIo-
methyl group" refers to methyl groups substituted by a
halogan atom, such as fluoromethyl, chloromethyl, ~bromo-
ethyl and iodomethyl,
It is known from the U5 patent specification Nos~
3,371,090 and 3,493,572 tha~ the compounds of ~he general
formula /I/ can be prepared by reacting 2-formyl-quinoxaline-
-1~4-dioxide or the diallcyl-acetal ~hereof with a reactan~
containing a primary amino groupO The reac~ion i5 un~avourable
because of the moderate yield /about 80 J0/ and tha relatively
long reaction time, which in csrtain cases, can be as long
as 24 hours. Besides, tha main reaction is accompanied by
different side-reactions, and the desired compound is
~ ~59~
~ 3 -
:
contaminàted with the side-products ~hus-formedO The puri-
fication of the end-product requires complica~ed operations
and can be carried ou~ only a~ the expense of high losses of
substance,
According to a fur~her known method the co~pounds of
the general formula /I/ are produced by reacting 2~formyl-
-quinoxaline-1,4-dioxide or the corresponding dialkyl-acetal
with a Schiff base /Hungarian pa~ent specification No, 171,738/~
~ Now i~ has been found that the compounds of the general
formula /I/ can be prepared economically in an excellent
purity by dehydrating a Z-hydroxyme~h~ quinoxaline-1,4-
-dioxide derivative o~ the general formula /II/
O OLI
C~I-Nl-l-A
wherein
A has the same meanings as above,
The dehydration can be carried out in two different
ways: either thermally, that is by heating the compound of
the general formula /II/, or by using a dehydrating agent~
When dehydrating under thermic conditions one prooeeds
preferably by heating the suspension of the compound of the
general formula /II/ in an indifferent solvent until no more
water is split off, As indifferent solvent preferably water,
aliphatic alcohols, such as isopropanol or butanol, aromatic
hydrocarbons, such as toluene or xylene can be used. The
~;~
47~3
~ 4 -
reaction is preferably carried out at the boiling poin~
of the solvent, generally at 40 C ~o 150 C~ When using
an organic solv~nt immiscible with water the ~ermal
dehydration can be carried ou~ by continually removing
the water obtained -From the system, e.g. in form of an
azeotrope, In this way the reaction can be followed, too,
When dehydra~ing according to the o~her metl70d, de-
hydrating agents generally used ~or such purpose /eOg,
polyphosphoric acid, sulfuric acid, calcium chloride,
etc./ are used,
The 2-hydroxymethyl-quinoxaline-1,4-dioxide dertvatives
of the general formula /II~ used as starting substances are
new compounds which can be prepared by reacting a Z-methylene-
-quinoxaline-1,4-dioxide derivative of the genaral formula
/III/ 0
~N ~,CH - Q
0
wherein
Q represents an oxygen atom or two alkoxy groups containing
1-4 carbon atoms each,
with a carboxylic hydrazine of the gsneral formula /IV/
A NH2 /~V/
wherein A has the same meanings as above,
As the dehydration of the compounds of the general
-- 5 ~
formula /IIJ is carried ou~ quickly, the side-product
formation is eliminated and the compounds of the general
formula /I/ can be obtained economically, almost quantita-
tively.
Further details of the ~nvention are illustrated
by the following non-limiting Examples:
~ s of the general formula
091 mole of 2-formyl~quinoxaline-1,4-di~xide dissolved
in water or dimethylformamide is reacted with 0~1 mole of a
compound of the general formula /IV/ in the presence of 2
drops of concentrated hydrochloric acid or piperidine. The
separated product is ~iltered off, washed wlth water and
dried.
~e~L
~9
28.0 9 /0.1 mole/ of 2-/~C-/methoxycarbonyl-hydrazino/-
-o~-hydroxymethyl/-quinoxaline-1,4-dioxide are admixed with
150 ml of water and the mixture is boiled for an hour under
stirring. Then it is cooled, the separated prodwct is
filtered off and washed with water. 25,4 g /98 ,~0~ of desired
compound are obtained.
~.p~: 257-258 C.
-- 6
Example 2
~
41,6 g /o.l mole/ of 2-/ ~/3,4,5-~rimethoxybenzoyl-
5 -hydrazino/- -hydroxyme~hyl/-quinoxaline-1,4-clioxide are
dehydrated in 250 ml of isopropanol, in the presence of a
drops of sulfuric acid at 50 C to 60 C, under stirring,
After cooling the reaction mixture the separa~ed product
is filtered off and washed~ 39~R g /98 %/ of desired compound
are obtained. M~p,: 255-256 C,
Example 3
-1,4-dioxide
-
27.2 g /Ool mole/ of 2-/Oc-/cyanoacetyl-hydrazono--
- ~-hydroxymethyl/-quinoxaline-1,4-dioxide are suspended
in 200 ml of toluene, and the reaction mix~ure is kept alt
1;20 C ~or an hour, Then it is cooled, and ~he separated
product is filtered of~, 26,0 9 ~97 t,Y~/ of desired compound
20 are obtained,
M,p.: 244-245 C
Example 4
2~
4.16 g /0.01 mole/ of 2-/~ -/3',4',5'-trimethexy-
benzoyl-hydrazino/~ hydroxymethyl/-quinoxaline-1,4-
-dioxide mixed with 40 g of polyphosphoric aciLd are
-- 7 --
allowed to react a~ 25 C for 3 hours, ~hen the reac~ion
micture is poured into a lo % cold sodium hydroxide
solution, The separated precipita~e is ~iltered o~f and
washed wi~h water until neu~ral. 38.6 9 /97 ~/ o~ desired
compound are obtained.
M,p.: 256-256.5 ~C.
The compounds listed in the following Table are prepared
by the methods o~ the previous Examples:
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n ~ cn In ~ n ~ In
i~a~ co ~ N ~1 (:~ ~ N O
. ~ ~ m ~ ~a~
Q C) I I I I I I I -r I I I I I I
O )a) ~ O CD r~ lcn u) o
OD ~ 0~ ~ ~Ln ~ O ~ i~ Da) ~o
~IC`l N N~IC'J NrJ N N ~1 C~l ~J C\l C~l C~l
~J u~ o m o m m m
~ ~ ~ o~ ~ ~ ~ mco
L C~ I o I ~ I I o I I o o o O o O o
o o Ou) o o o O ~o o O In m Ln N ~ LnIn
E 0~ COcnCO ~ U)t~
~1)
Y- _I
O O~I N ~1_I~1~I N ~ 1 ~ N ~t
a~ o x
~1
O
~1 ~:
0 10
E r Q ~ ~I
3 L 0 L L L L o Ll_ o _I L~D L o L
,1 ~ Q G) ~GlID La~ ~ C o al C ~ C Q~
O ~JJ~JJJ Q ~
~D ~ L 0 ~ 0 ~ O ~ 0 C 11) ~~1 ~ S:t3
~: ~ O ~ X ~ O~
O) E.1:1 E
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>`
N ~I N
I ~ J ~ N O
I ~ rl ~ O I I --1~! I N I U~ I
Z IUl L O r Q Q >~ N I N
d ~ ~i9 3 d o ILn l~n ~ ~ Im ~ ILn ~ Im
O O ~1 0 ~ 1 L L I L ~ I L T
6 I I I I I I ~~D rl rl~D 3
O I I C~~) R Q O ~ ~0 ~ C.~
I II I I I I O O O O O O ID C~ O
I X I I I I :r ~ c
z z z z z z z z ~
Q
E OLn ~ O
X ~ ~I r-l ~Jr~l ~1 1~1r I~11--l r -l
111
~r ,.
~ ~ 54~
g
~ ~ o ~
. ~ ~ ~O
Q
. O I I ~1 1 0 1 ~ I r~) I I I I
:~ ~ t` ~ ~ ~ ~ > O
3 U~ U) 10 0 0 Il In
~ ~ a~ n ~ o o C)~
a~ ~ o o In In~1 $ O In o o ~ ~1 o n
E ~ a Cll ~1 ~ In QD Cl) /:T~
I_
o ~1
O
O ~
a)z x
_l
L Q~I Q a~ o U~ a~ a) L L
E L ~ O O ~ O ~ C SJ ~ Il) ~ ~ ~
::S a) ~ L C C L ~ W 3 0 0 5
~1 ~IISa.t~ Q~ Q3~
O ' ~1 0 ~ O:~`
Oi~ ~ x
s ~ 1 n Xrl 0~3
Z N
:~ I
O U) 3~
c~ L o ,1 ~` --I N
I I ~ Q ~ O ~
I I C) L D rl 0 ~15 ~1 ~ I ~ I
Z Z ~t~ Z t~ O
I I Ia) I I I Q ~ N
O ~ C ) O O ~) I ~ C O ~ O
~ O .
I I I I I -r
Z Z Z Z Z Z Z Z I Z Z Z
o ~1 ~ ~ ~In ~I~ a~ O~ o ~
X ~ ~I C~ 1 N
IIJ
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