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Патент USA US2133787

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Patented 0a. is, 1938
‘UNITED s'rArss
} ’
2,133.18‘: .
Elmore Hathaway Northey, Bound Brook, N.‘ 1., '
assignor to The Calco-Chemical Company, Inc.,
‘Bound Brook, N. 1., a corporation of Delaware
No Drawing. Application January 1l,'-193,8,
Serial No. 184,415.
'13 Claims.
This invention relates to di(aminoarylsul
phon) amides and methods of preparing them.
(or zen-44's)
be situated at any}; slut in the chain. For thera
- pcutic purposes, the compounds in which the
_ Monosulphonamides of aromatic compounds amino group is para to the SO: group are usually
have- been prepared and some of them have preferable and constltute'a preferred species. In
5 achieved great practical importance as bacterio
stats. Notably, the p-aminobenzenesulphonam
ide, (sulphanilamide), is widely used as a chemo
therapeutic against streptococci, gonococci and
similar bacteria. The > monosulphonamides - have ‘
10 also been used as intermediates for'the produc
tion of azo dyes. A serious disadvantage of the
commercially exploited monoaminosulphonam
ides, such as sulphanilamide, has lain in their
relatively high toxicity. As a result, the di?er
15 ence between the minimum e?ective dose against
such organisms as streptococci and the dose which
produces serious results or even deathis narrower
than is desirable and a number of serious second
ary toxic reactions have occurred.
20 The present invention is directed to aminodi
sulphonamides, many of which possess the im
portant property of increased therapeutic effec
tiveness against bacteria withoutv increased tox
icity and generally with decreased toxicity. The
25 compounds are therefore more useful as thera
peutic agents because the greater difference be
tween the eifective dose and fatal dose renders
their use much safer in practice.
_ The present invention is limited to di(amino-*
30 arylsulphon) amides and, in general, covers com
pounds having the following general formula:
usually desirable, although not essential, that they
be soluble and therefore compounds in which X V1().
in the formula above given is an’ alkali metal, -'
magnesium, calcium or other base yielding solu
ble products are preferable.
v '
For many purposes high solubility is not neces- “
sary and salts of other bases may be used which 15 '
are insoluble‘ or only sparingly soluble. Such
bases include heavy metals such as silver, gold,
mercury. bismuth, antimony, lead, aluminum,‘
iron and arsenic compounds which are capable of
forming salts.» Other insoluble compounds ‘in~ 20
clude the alkyl and aryl compounds in which alkyl
or aryl replaces the remaining hydrogen'of the‘ .
amino group. The possibility of preparing salts
of heavy metals and similar compounds is of great
importance therapeutically as many of these 25
metals exert powerful actions against bacteria
and other disease-producing organisms. Such
compounds where the bacteriostatic action of the '
diaminoarylsulphonamidesis reenforced or sup
plemented with therapeutically active metals
metal compounds such as for example arsenicals
greatly increase the ?eld of utility of ‘the com
pounds of the present invention. ‘
where R is an aminoaryl containing an amino
or substituted amino group, R’ is an aminoaryl
and X is hydrogen, a metal or an
the case of azo dye intermediates, other positions 5
of the ‘amino group are frequently preferable.
For the purpose for which the ‘compounds of.
the present invention are particularly useful, it is,
I or aryl
While the invention is not limited to di(amino-
For therapeutic use, it is usually desirable to
provide a substantially neutral medium; accord;
ingly, the salts are preferable to the acids 'for this
purpose. However, for other uses such as azo
_dye intermediates, the compounds may be present '
in the form of their acids. that is tos'ay where X
is hydrogen, and the present invention is there 40
.arylsulphon) amides, this class is the preferred 7 fore in no sense restricted to salts.
one and corresponds to-the formula given above
The compounds of the present invention are
where both R and R’ are aminoaryl groups. new chemical compounds and are .claimed as
This preferred class includes some of the most such, regardless of the method by which they have
45 effective therapeutic agents covered by the pres
been prepared. . I have found, however,vtha_t good .45
ent invention. Most of the cheaper compounds ' yields of products of high purity may. be obtained,
belong to the benzene and naphthalene series particularly in the case of the di(aminodiarylsul
but the invention is not limited‘to mono- and di
phon) amides, by bringing about reaction between '
nuclear compounds andQon the contrary, includes an acylaminoarylsulphonchloride and ammonia
50 tri- and other poly-nuclear compounds such as or a monosulphonamide. This process is there- 50
those of the anthracene, phenanthrene, ?uorene fore also covered as a speci?c feature of the pres
and similar series.
The position of the amino group on the radical
R in the formula given above may vary and in its
55 broader aspects the invention vincludes com
pounds inwhich the amino group is ortho, meta
ent invention.
The invention will be described in greater de
tail in conjunction with the following specific
examples which describe the production of typical 55
compounds falling under the present invention.
or para to the S02 group-in the case of mono
The invention is, however, not limitedto the de
nuclear compounds and in the alpha or beta posi . tails therein set forth. Unless otherwise ex- '
tions in the case of naphthalene compounds. In pressed, parts are by weight and parts of water
60 the case of aliphatic compounds, the group may
are by corresponding volume._
‘ -
atures above 300'’ C. On diarotisation with
nitrous acid, a tetrazo compound is obtained
which may be coupledwith the usual coupling
components to form azo dyestuifs.
Exams: 1
Di(N-acetillsulphanil) amide
(cmoonnos om=Nn
Salts other than the sodium salt may be made
inthe case of some of the stronger bases by re
1 mol. of anmionia is dissolved in 150 parts of
water at 10° C. and 2 mols of freshly prepared
action of a carbonate or hydroxide of the base
N-acetylsulphanilylchloride paste are gradually with disulphanilamide. and in other cases, by
added with vigorous agitation. Su?lcient 50% “double decomposition in aqueous solution of the 10
sodium salt of disulphanilamide with a suitable
10 caustic soda solution is added to maintain a pH
salt of the metal.
between 10 and 11.5 and ice is introduced from
time to time to keep the temperature between
32‘and 37° C. After. all of the N-acetylsulpha
nilylchloride has been‘added and the pH has
disulphanilamide and Sod. for sodium. ' In' re
been ?nally adjusted by means of caustic soda,
stirring is continued for about one hour.
The following table gives a number of repre
sentative salts and their method of preparation
and properties. The abbreviation Dsa. is used for
ferring to the solubility, s. is used for soluble,'_v.
for very, sl. for slightly, mod. for moderately and
ext. for extremely. In the table under method of
preparation. the reaction takes place in aqueous
The reaction mixture is cooled to 10° C. and
solid matter ?ltered oil. The precipitate consti
tutes crude sodium di(N-acetylsulphanil) amide.
solution except where speci?cally noted.
20 It is puri?ed by recrystallization from hot water
‘ Salts or duuipnanamue
Method of preparation
> '
Lithium ................. _- Dsa.+LiO0r
Hot water
small white ?at rods or plateau...“
V. I.
plates .......... ..
.......... -lee ............. --
V. I.
V. I.
Ext. I.
Mod. I.
L ht green needles Lgreen thin plates.
Mod. I.
Ext. I.
Bl. I.
V. I.
White gins ' ....... .-
Bl. s.
V. I1. I.
81. s.
V. II. I.
White diamond shape plates
Bl. I.
V. I1. I.
.......... .-
81. I.
V. I1. I.
White rods and medium...
Ferric ..... --
Li ht yellow (path-n
_____ __
' lih?on
i ................. _-
Di-n-amyl ammonium_.-__ Sod. Dsa.+ CIH|8INEHQI
8!; L
V. sl. I.
lied. I.
V. I.
needles ............ .-
Moncyn-amyl ammonium _
Gold ‘at.’
Tetrahedral and spherical segments.
81. I.
51. I.
V. IL I.
Triethanol ammonium---_ Dsa.+(H0. HI. HQiN_.----._..-_. Not readily crystallisable syrup_-.--
Ext. s.
Ext. I.
1 In cold solution is precipitated as‘ bronze scales which spontaneously change to the above.
’ Apparently quite light stable.
in which it is very soluble. The free diiN-acetyl- '
' sulphanil) amide may be obtained by. acidifying
I Exam“ 3
the sodium salt with a mineral acid. The free
45 diamide is almost insoluble in dilute acids and
melts with decomposition at 284-286‘ C.
Instead of using N- acetylsulphanilylchlorlde
and ammonia, equi-molecular quantities of N
acetylsulphanilylchloride and N-acetylsulphsnil
50 amide may be used, the procedure being the
same and the same product being produced.
Exams: 2
60 mol. of the crude paste with 6 mols of caustic
soda in 200 parts of water until no further in
crease in diazotizable amine is noted. fThe hy
drolysis mixture‘is then cooled to 10' c. and the
crude sodium disulphanilamide ?ltered on.
The crude product may be puri?ed by recrystal
lization from hot water in which the compound
of de
is very soluble, preferably in the '
colorizing carbon.
The mother
1 mol of metanitrobenzenesulphonamide is dis
solved in 1600 parts of water containing 16 parts
of soda ash and 30 parts of caustic soda, the
temperature being 45° C. 1.3 mols of metanitroe
bensenesulphonchloride are then added during
one .half hour while maintaining apI-I of 10-11
quired. During reaction the temperature is main
tained between 45 and 60?’ C. and after reaction is
The sodium di(N-acetylsulphanil)amlde de
scribed in Example 1 is hydrolyzed by
by ‘the addition of caustic soda solution as re
Sodium disulphanilamidc
s 0, =N—n
here may he
treated with acid to produc '"a pH of 2 to 3 at
'70 which pH the free amide sh ws its minimum solu
bility. At body, temperature, the solubility of
sodium disulphanilamide in water is 20 gs. per
100 cc. and at 10° 0., this .has dropped to 9.6
gs. per‘ 100 cc. The product melts ‘with decom
pomtion to a characteristic bluecoloratetemper
completastlrrlng is continued for 1 hour. The
mixture is then cooled, the crude product crystal
lized out and filtered. Puri?cation is effected by
recrystallization from water and results in sodium
di(metanitrobenzenesulphon) amide.
, The nitro compound produced above is reduced
in 21,5 times-its weight of 28% ammonia by pass
ing a stream of'hydrogen sulphide through the
suspension while vigorously agitating. At ?rst
cooling is provided, but as the reaction moderates, '
the mixture is heated at a slow boil under a re?ux ~
condenser with continual passage of hydrogen
sulphide for 1 hour. After reaction is substan
tially complete, air is passed through the hot so
lution to remove excess ammonia and to oxidize
sulphides to sulphur. Thereupon the mixture is
madeealkaline to phenolphthalein with caustic
soda and the sulphur ?ltered oi‘f. Hydrochloric
' 2,133,787 '
solution to 4.5 to 5 and crude dimetanilarnide is concentrated hydrochloric acid. The precipitated
?ltered oil. Puri?cation is e?ected by recrystal ' salt is ?ltered oil and the ?ltrate discarded.
lization from solution in alkali, preferably after
The paste is hydrolyzed by boiling for a half
treatment with activated charcoal. The product
hour with 1200 parts of 18% hydrochloric acid
' melts with decomposition to a deep blue green
after solution is complete. The reaction mixture is
then neutralized with caustic soda to a pH of 4 to
5 and a tarry mass separates out. This is dissolved
liquid above 330° C.
inaminimumamount of hot water containing suf- -
- Metanitrobenzenesulphonzrl(N-metanitroben
zenesulphonylsulphanil) amide
1 mol of sulphanilamidej is suspended in 500
. parts of water and 2 mols oi metanitrobenzene
sulphonylchlorlde is gradually added with agita—
tion. A pH of 9 to 11 is maintained by the addition
of 50% caustic soda as necessary, the temperature
being kept at 40-50° C. by the addition of ice.
After the addition is complete and the pH is ad
justed, the reaction mixture is stirred for an hour
and then strongly acidi?ed and the precipitate of
crude met-anitrobenzenesulphonyl(N-metanitro
benzenesulphonsulphanil) amide ?ltered oil.
Sodium metaniKN-metanilylsulphanil) amide
of the'di- and tri-sodium salts and a nitrite titra
tion shows a molecular weight of 698 which corre- _
sponds to a theoretical weight for‘ the trisodium 20
salt of 703. The analysis for sodium shows 9.5%
as against 9.81% called for by the theory.
Sodium ‘sulphanil(N-sulphanilylsulphanil)- .
NEQsomn-Os ol-ils-s Qr-O-Nm
L1: 5
?cient 50% caustic soda solution to bring the pH
up to 9_t'o 10. Decolorizing carbon is added to .10,
clarify, the mixture cooled and three volumes of"
alcohol added. A crystalline product which pre
cipitates out is ?ltered oil’ and washed with alco
hol. Puri?cation may be effected by repeated
solution in small amounts of hot water and treat 15
ment with decolorizing carbon and precipitation
with alcohol. The resulting product is'a mixture
The nitro compound produced in Example 4
35 is dissolved in 800 parts of strong ammonia and
reduced by passing a rapid stream of hydrogen
sulphide through it at ?rst with cooling and then
with the addition of heat to bring the reaction
mixture near boiling. After passing hydrogen sul
phide through for about 11/2 hours, air is passed
through the reduction mixture to remove hydro
gen sulphide and oxidize ammonium sulphide pro
duced to sulphur. The sulphur is ?ltered o?fthe
?ltrate acidi?ed and the crude product ?ltered
45 off. Puri?cation is effected by dissolving the
crude product in a caustic soda solution, neutral
ized to a pH of 7, ?ltering o? solid material,
treating with decolorizing carbon and reprecipi
tating with acid. If desired, the puri?ed product
may be dissolved in a minimum amount of hot
water, using caustic soda and adjusting to a pH
of 7. On cooling, the sodium salt crystallizes out
and can be further puri?ed to complete whiteness
by recrystallization from hot water. Titration by
nitrite gives an equivalent weight of 251 as against
a theoretical equivalent of 252.
Emu: 6
1 mol otsulphanilamide is dissolved in 1000 80
parts of water at 35° C. with the addition of
sui?cient caustic soda to bring the pHv to 11. 2.4
mols of freshly prepared acetylsulphanilylchlo
ride paste is then added during 20 minutes while
maintaining a pH at 10 to 11 by the addition of 35
50% caustic soda solution as required. Su?lcient
ice is added from time to time to maintain the
temperature at 35-45° C. and stirring is continued
for an hour after the addition is complete.
The product is hydrolyzed by adding 200 parts 40
of caustic soda to the reaction-mixture and boil
mg for two hours until there is no further in
crease in diazotizable amine. The hydrolysis
mixture is neutralized to a pH of 7.5, cooled and
the crude product crystallized out. Puri?cation is 45
effected by repeated recrystallizations from hot
water using decolorizing carbon. Tltration by
nitrite gives a molecular weight of 256 as against
252 for theory.
If the free amide is desired, it may be pro-‘
duced by acidi?cation of a solution of .the sodium 50
The amide comes down as a tarry mass
which crystallizes on rubbing in alcohol. Nitrite
titration shows an equivalent weight of 243 as'
against 241 for theory.
Exam .8 v
Methyl di(N-acetylsulphanil) amide
Tn‘sodium Di(N-sulphanil_ylsalphanil) amide
[um-Os m-rir-G-s 0,] =N-Na
1 mol of sodium disulphanilamide prepared as
described in Example 2 is dissolved in 1700 parts
of water. 50 parts of soda ash are added and then
2.2 mols of freshly prepared acetylsulphanilylchlo
ride paste are introduced with agitation, a pH of
8 to 10 being maintained by the addition of 50%
caustic soda solution as necessary. The tempera
70 ture is maintained at 35-40° C. by external cooling
and stirring at the same temperature is continued.
for‘2 hours after the addition 01' the acetylsul
l-mol of sodium di(N-acetylsulphanil)amide is
suspended in 2000 parts of dry'xylene and two
‘mols of dimethyl sulphate added. The mixture
is heated under a re?ux condenser for three
hours and the solid produced. ?ltered off, the ?l 65
trate being discarded. The solid is suspended in
3000 parts of water and warmed with the addi-‘
tion of 50% caustic soda solution until the solu
tion is permanently alkaline to 'phenolphthalein.
Insoluble material is ?ltered off and constitutes 70
the crude methylated product.
phanilylchloride is complete. The reaction mix- ' ?ltrate and reprocessed.
ture is then heated to 90° C., clari?ed andthe
75 clari?ed liquid acidi?ed with about 400 parts of
Unmethylated ’
material can be recovered-by acidi?cation of the
The crude material can '
be puri?ed by dissolving in glacial acetic acid and
precipitating by dilution with water. 0n heat 75
ing, the product decomposes inde?nitely above
210° C.
4. Disulphanilamides having the following for
Rama: '9
Naphthionuup-toluenesulphanil) amide
in which R is a member of the group consisting of
hydrogen, anacyl and an aminoaryl radical and
X is a member of_the group‘ consisting of hydro 10
gen, a metal, an alkyl radical and an aryl radical.
5: Di(am1nobenzenesulphQnyI)am1de having
the following formula:
1 mol of acetylnaphthionamide is suspended in
15 1000 parts of water and the pH adjusted to 10
to 11 by the addition of caustic soda. 1.5 mols of
over ‘ a
1‘ ups
period of 2 hours while maintaining the reaction
mixture at 60-65’ 0., strong caustic soda solution
20 being added to maintain the pH between 9 and in which x is a member of the. group consisting of
10. The mixture is then neutralized to pH of . hydrogen, a metal, an alkyl radical and an aryl
7 .5 and clari?ed with decolorizing carbon. After
clari?cation, the solution is made acid to Congo
with hydrochloric acid and the precipitate iii
25 tered off. This is crude paratoluenesulphonyl
6. Disulphanilamides having the following for
The product is hydrolyzed by dissolving in 1000
' parts of water containing three mols of caustic
soda and boiling for 2% hours. The hydrolysis
30 mixture is acidi?ed until it turns Congo red and
is cooled, the crude product being ?ltered o?.
Puri?cation is effected by recrystallization from
dioxane using decolorizi'ng carbon. The com
pound melts with decomposition at 156-15'1° C.
35. What I claim is:
in which x is a member of the group consisting of
hydrogen, a metal, an alkyl radical and an‘ aryl
'I. A soluble salt of 'disulphanilamide having the
following formula:
1. Disulphonamides having. the following for
/ x
iv-s o,
in which R is an aminoaryl radical, R’ is ‘a mon
onuclear aryl radical and X is a member of the
group consisting of hydrogen, a metal, an alkyl
45 radical and an aryl radical.
2. Diiaminoarylsulphon) amides having the fol
lowing general formula:
amino group.
9. A method of preparing a di(aminoarylsul
mols of the acetylaminoarylsulphonchloride being
in ,which R is an aminoaryl radical, R’ is a mon
onuclear aryl radical containing at least one
amino group or substituted amino group and x
55 is a member of the group consisting of hydrogen,
éaa metal, an alkyl radical and an aryl radical.
3. Di(amino_arylsulphon) amides having the fol
prgsentfor each mol. of ammonia and hydrolyzing
th acetylamino group.
10. A method of preparing a di(aminoarylsul
phon) amide. which comprises reacting a nitro
arylsulphonchloride with a compound included in '
the group consisting‘ of acetylaminoarylsulphon
amides and nitroarylsulphonamides, reducing all
nitro groups to amino groups and hydrolyzing
any acetylamino group present.
11. Disulphonamides "according to claim 1 in
which X is a heavy metal.
12. Di(aminoarylsulphon) amides _ according to
in which R is hydrogen, an acyl or an aminoarylé
06 sulphonyl radical, R’ is an aminoaryl radical and
x is a member of the group consisting of hydro
gen, a metal, an alkyl radical and an aryl radical.
aminosulphonchloride with ammonia, at least two 50
/ x
nrm<:>s {.N
8. A method of producing a di(aminoarylsul- I
phon) amider which comprises reacting an acetyl
aminoarylsulphonchloride wi an acetylamino
arylsulphonamide and hydr yzing the acetyl
' phon) amide which comprises reacting an acetyl- '
R'—8 01
~ lowing formula:
in which X is a metal forming a water-soluble
salt of disulphanilamide.
claim 2 in which X is a heavy metal.
13. Disulphanilamides according to claim 6 in 65
which X is a heavy metal
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