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Патент USA US2107712

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Patented Feb. 8, 1938
2,107,712
UNITED STATES PATENT’ OFFICE; '5
2,107,712
GUANIDlNO AND BIGUANIDINOI DERIVA
TIVES 0F CYCLIC ETHER COMPOUNDS
Bruno Puetzer, Albany, N. Y., assignor to Win
throp Chemical Company, Inc., vNew York, _
N. Y” a corporation of New York .
f
No Drawing. Application June 7, 1934, Serial ,
No. 729,478. In Germany June 9, 1933
7 Claims. (Cl. 260-125)
This invention relates to the manufacture of
guanidino and biguanidino derivatives of ether cordance with the following reaction scheme
compounds which are. therapeutically valuable when using'an amino substituted ether, of; the
benzene series as the reacting component:
media.
In accordance with the present invention sub
I 'Y
'
5
stances of a considerable action on bacteria and
protozoa are obtainable in accordance with the
The biguanidino compound is formed mamm
methods hereinafter indicated by the manufac
ture of guanidino and biguanidino derivatives
> ance with the following reaction scheme: .
'
'
,10 of ethers in which a six-membered nucleus is
linked to a second at most bicyclic ring system
by means of at most 2 ether-like bound oxygen
or sulfur atoms.v The six-membered nucleus ~mentioned above is preferably a nucleus of the ‘
15 benzene series, however, also hydrogenated ben- _ The reaction‘is vpreferably carried out with heat
zene nuclei may be present in the new products. ing. Water or water-soluble alcohols are pref
erably used as solvents.
‘
" .
> v
' "
The other nucleus combined with the six-mem
In further development of my present inven
bered nucleus by at most two ether-like bound
oxygen or‘ sulfur atoms is likewise preferably a tion I have found that the new guanidino and bi
20 nucleus of the benzene series, but also in this guanidino derivatives of the ethers specified are
case hydrogenated benzene nuclei furthermore ' also obtainable by reacting upon 'the'said amino
bicyclic ring systems, such as naphthalene, are ‘substituted cyclic etherswith S-alkyl' or, S-aryl
suitable for the production of the new guanidino alkyl-isothiourea ethers in‘ which‘ reaction the
and biguanidino derivatives of the ether com-- guanidino compound‘ is formed while a mercap
pounds.
The cyclic radicals may be connected - tane or arylmercaptane compound is split off.
25
similarlyjbiguanidino compounds are obtainable
in this manner by reacting upon N-guanyl sub~
‘ -thioethers, or may be further combined by a stituted -S-alkyl or rS-arylalkyl-isothiourea- ethers
second oxygen or sulfur atom as, for example, inv with the said amino substituted ethers. The re
action, for instance, performsin accordance with
30 the diphenylene-dioxides or -disul?des.
with one another by one oxygen or sulfur atom,
as, for example, in the diphenylene-lethers or
The nuclei of the new compounds may be fur
the following reaction scheme:
,
‘
30
‘ther substituted by monovalent substituents,
such as alkyl ‘groups, for example, the methyl,
ethyl, isopropyl ‘ and allyl group, and alkoxy
35 groups of the same kind. Other substituents, are,
for instance, halogen atoms, preferably chlorine,
bromine and iodine, the nitro group, alkylamino
groups, and the like. It may be mentioned that
35
Alternatively the 'new products could be ob
tained by reacting'upon a cyanamino compound
of an ether as speci?ed with ammonia, primary
or secondary amines or guanidines, for instance,
alkylaminoalkyl radicals and one of the nitrogen ammonia or amines are bound by a cyanamino
atoms of the guanidino or biguanidino radicals ' diphe'nylether while forming a corresponding
may be the member‘ of a heterocyclic nucleus. guanidino-diphenylether whereas guanidino. is
' ‘also the guanidino or biguanidino radical may
40 contain substituents, for instance, aminoalkyl or
' One or more of the guanidino or biguanidino
45 radicals may be present in the new compounds
bound by the said cyanamino-diphenylether
while» forming the corresponding biguanidino-di
de?ned above.
In accordance with the present invention the
new guanidino and biguanidino derivatives of
rivatives of ethers may be reacted with ammonia,
[the ethers speci?edare obtainable by reacting
primary or secondary amines or guanidines in
pheny'lether.
'
"
~.
_
Furthermore, thioureav or guanyl thiourea de
upon an amino substituted ether, in whichv a
the presence of a condensing agent, such as
six-membered nucleus is linked to a second at
metal compounds, for instance, lead hydroxide, '
most bicyclic ring system by means of at most
in which case the‘ corresponding guanyl or bi
two ether-like bound oxygen or sulfur atoms, guanyl compound is formed whilehydrogen sul
with cyanamide or dicyandiamide in the pres
?de is split off, for instance, guanidinodiphenyl
ence of a solvent. The reaction performs in ac I ether is obtained by reacting upon a thiourea di
5
2,107,712
which is now soluble in acids is treated in the
‘Iihenylethernwith ammonia ‘inmaccordance ' with above described manner.
Example '2.-18.4 grams of 4-aminodiphenyl
the; following equation :1 1 '
ether, 23 grams of - hydrochloric acid (speci?c
gravity 1.08) and 9 grams of dlcyandiamide are
by reacting upon the same startingmaterial with . heated to boiling for 20 minutes. The é-biguan
guanidine,-' 'biguanidino-diphenylether' ‘is ob
idinodiphenylether-hydrochloride forms whitish
crystals when recrystallized from water ‘which
tained.- ~
'
fThe ‘guanidino
.or biguanidino derivatives of
m the ethers furthermore can‘ be obtained by com—
melt at 249° 0..
'
20. grams of 4,4’—diaminodiphenylether, 46 10
grams of hydrochloric acid (spec. gravity 1.08)
bining two ‘cyclic components at least one of
which ‘contains the‘guanidino or biguanidino rad
and 18 grams of dicyandiamide are heated to
ical by means‘ of an oxygen-or .sulf-ur'atom, for boiling for one hour. After cooling the mix
instance, by-re'acting-upon a guanidino ‘or biguane ture is diluted with water, rendered alkaline and 15
the separating precipitate is recrystallized from
idino-phenolate or thiophenolate with a cyclic
methylalcohol. The 4,4’-bis-biguanidino-diphen
yi)ether forms whitish crystals which ‘melt at
15 compoundsubstituted by a reactive halogen atom,
_ _ such as a nitro, -'-haloge'n, .-benzene ‘or
, 20
-pyridine, '
2 2° C.
In an analogous manner there are obtained in
or ‘with an 'arylalkyl halide.
The valuable bactericidal properties of the new
guanidino'" and "biguanidino- derivatives of the
ethers speci?ed‘ obviously reside in the simulta
the form of whitish crystals 2-biguanidino-4’ 20
methyl-diphenylether, melting at 158° C., 3-bi
guanidino-3’ ,5’ -dimethyldiphenylether melting at
neous presence of an ether-likelinkage of two
' cyclic- radicals, on theyonehand», inv the presence
or at least one guanidino or biguanidino group
119° C_., 4-biguanidino-2’-methyldiphenylether,
melting at 150° C., 4-biguanidino-4’-methyldi—
phenylether the hydrochloride of which melts at
attachedrto a nucleus, on the‘other hand,_since
guanidino- compounds, which do not contain the
ether-likedinkage between two cyclic radicals,
do not show-a ‘considerable bactericidal action.
242° C.,~ 4-biguanidino-2,4’-dimethyldiphenylether
melting at 149° C., 4-biguanidino-3’,5’-dimethyl
diphenylether melting at 181"v C., (hydrochloride
melting at 224° C.), 4-biguanidino-2,3',5’-tri 30
methyldiphenylether melting at 145° C. (lactate
The invention ‘is vfurther illustrated ' by the fol
lowing; examples without being limited thereto:
v'Example1‘1.'---3.6 grams .of sodium cyanamide
'
are "suspendedfin 25 cos. of alcohol and-treated
with 7.7 grams of’ concentrated hydrochloric acid
while cooling. . The sodium chloride which pre
I” cipitates isisucked off
and the ‘?ltrate after vthe ,
meltingat
8'7.“ C.) , a-biguanidino-li'~chlorodiphen
ylether (hydrochloride melting at 243° C.), 4-bi
guanidino-3 ' -ch1oro-4 ' -methyldiphenylether (hy
drochloride melting at 202° 0.), 4-bi‘guanidino-2 35
chloro-3’,5’-dimethyldiphenylether melting at
‘addition ‘of ‘12l5igrams of 4=—amino—3'._5’-dimethyl- . 154° C. (lactate melting at 163° C.; dihydrochlo
‘ diphenyletherhydro-chloride is heated in a bomb.
tube for-5 hours-to 140-150’- C. The'alcohol is
then‘ evaporated in vacuo, the residue is dissolved
' in dilute-hydrochloric acid andthe solution which
has been renderedalkaline is extracted with
ether. ‘Thecolorless crystals of the 4-guanidino
ride‘melting at 228° C.) .
Example 3.-—13 grams of 4-’methylamino-3',5'
dimethyldiphenylether-hydrochloride, 25 cos. of
water and 4.5 grams of dicyandiamide are heated 40
to boiling for one hour.
The mixture is then
rendered alkaline, extracted with ether and the
residue is recrystallized from alcohol. The
3’.5'é-dimethyldiphenylether which are obtained‘ ether
4-a-methy1-biguanidino - 3' ,5’ - dimethyldiphenyl
- afterdryingQthe-ethereal extract with potassium ether
forms whitish crystals melting at 187° C. 45
45 carbonate and evaporation of the'ether melt at
In
an
analogous mannerithe 4-a-diethylamino
.- ' 161° C, on recrystallization- from benzene-'liigroin.
‘The . same ‘compound? is obtained. when treat»
iing I4-aminoe3',5?edimethyldiphenylether with S
ethylisothiour‘ea-hydrobromide and decomposing
m the hydrobromide formed with alkali."
'The' same compound is obtained when start
ing with 4-cyanamino-3',5'-dimethy1diphenyl
ether melting at 120°- C. 6 grams of this com~
- pound‘areheated‘with 20 grams of 21% alcoholic
ethylbiguanidino-3',5'-dimethyldiphenylether is
obtained when starting with -4-diethylamino
ethylamino - 3',5’ - dimethyldiphenylether-dihy
drochloride. It forms whitish crystals melting at 50
142° C. Its complex copper salt forms raspberry
colored crystals melting at 192° C..
1
Example 4.--15 grams of 4-amino-4’-chlorodi
'phenylsul?de, 65 cos. of normal hydrochloric acid
and 6.5 grams of dicyandiamide are heated to 55
55 ammonia linia closed vessel'for .12 hours to 120°C. 'boiling for 2 hours‘. After cooling the hydrochlo
ride which has precipitated is ?ltered with suction
> - Thersolutionis ‘dried in vacuo,~the_residue is dis
’ nsolved'in dilute ‘hydrochloric-acid and treated in and decomposed with dilute caustic soda solution.
The
vthe manner/described above. '
Theinew-Jcompound can also ‘be obtained when
‘ m‘ employing the 4sthiourea—3f‘,5’+dimethyldiphenyl
4 - biguanidino - 4’ - chlorodiphenylsulphide
crystallizes from alcohol in whitish crystals melt 60
ing at 157° C. The dihydrochloride melts at
230° C.
Example 5.--15 grams of 4-diethylaminoethyl
amino-diphenylsul?de, 23 grams of hydrochloric.
- .rnelting at 151° .C.‘ as starting material.
A solu
acid (spec. grav. 1.08) and 4.5 grams of dicyandi
65
ftionxoi '9 grams ofthis substance is digested in amide are heated to boiling for 2 hours. The
50*ccs. of‘ methanol with *excess leadhydroxide aqueous solution is then rendered alkaline and
andz-50ccs. of alcoholic ammonia (21%).. The extracted with ether. The 4-a-diethylamino
solution is kept-at ordinarytemperature for some ethylbiguanidino-diphenylsul?de is precipitated 70
drying and concentration of the ethereal ex
0 hours and then shortly heated to ‘id-60° C. vThe after
tract by the addition of petroleum other. It crys
alcoholic solution is then suckedgo? from lead tallizes
from benzeneligroin in whitish crystals
- sul?de while hoti-and'fdried in vacuo. ‘ The residue
melting
at 117° C.
is again‘ heated with excess alcoholic ammonia
Example 6.-22.9 grams of 4-aminobenzyl
tof120° C. for several hours in a~ closed vessel.‘ The 'para-toluylsul?de, 23 grams of hydrochloric acid 75
76‘ alcohol ‘is evaporated .in 'vacuo and the residue
(spec. grav._1.08) and 9
3
are heated to boiling for
water but soluble in organic solvents and are
soluble in water in the form of their salts.
4. The compounds of the formula:
precipitated by means of dilute caustic soda solu
tion.
The 4- iguanidinobenzyl-para-toluylsul
?de crystallizes from alcohol in whitish crystals
melting at 177° C.
I claim:
1. The process which comprises reacting upon
an amino-substituted ether in which a six-mem
bered carbocyclic nucleus ~is linked to a second at
al-x-m
wherein R1 stands for a six-membered carbocyclic
nucleus, R2 stands for a six-membered carbocyclic
nucleus, one of the said nuclei being substituted
by a substituent selected from the group consist
ing of the guanidino, biguanidino and the corre
sponding N-alkylated groups, and wherein X 10
most bicyclic ring system consisting of six-mem
15
bered carbocyclic rings by means of ‘ an atom se
lected from the group consisting of oxygen and
sulfur with an amide compound selected from the
group consisting of cyanamide and dicyandiamide
the free bases insoluble in water
but soluble in organic solvents and are soluble in
15
water in the form of their salts.
in the presence of an inert solvent.
5. Mono-biguanidino-diphenylethers, w hi 0 h
products are in the form of the free bases insolu
2.
The
process
which
comprises
reacting
upon
20
an amino-substituted ether in which a six-mem-_ ble in water, but soluble in organic solvents and
bered carbocyclic nucleus is linked to a second are soluble in water in the form of their salts.
6. The process which comprises reacting upon 20
six-membered carbocyclic nucleus by means of
an. atom selected from the group consisting of an amino-diphenylether with an amide compound
selected from the group consisting of cyanamide
.25 oxygen and sulfur with an amide compound se
lected from the group consisting of cyanamlde and dicyandiamide in the presence of an inert
and dicyandiamide in the presence of an inert solvent.
25
solvent.
'
7. The compounds of the formula:
.3.’ The compounds of the formula:
ELK-R2
30
R1—X-—R2
wherein R1 and 1'12.2 stand for nuclei of the benzene
wherein R1 stands for a six-membered carbocyclic
nucleus, R2 stands for an at most bicyclic ring
'
series, one of the said nuclei beingv substituted by
system consisting of six-membered carbocyclic
rings, at least one of the said nuclei being substi
from the group
35 tuted by a substituent selected
consisting of the guanidino, biguanidino and the
corresponding'N-alkylated groups, and wherein
X stands for an atom selected from the group
consisting of oxygen and sulfur, which products
40 are in the form of the free bases insoluble in
a substltuent selected from the group consisting
of the guanidino, biguanidino and the corre
sponding N-alkylated groups, and wherein X
stands for an atom selected from the group con—
sisting of oxygen and sulfur, which products are
of the free bases insoluble in water, 35
but soluble in organic solvents and are soluble in
waterin the form of their salts.
BRUNO PUETZER.
40
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