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Patented Nov. 19, 1946
I 2,411,495
Max Dohrn, Berlin-Charlottenburg, and Paul
Diedrich, Finkenkrug, Osthavelland, Germany,
asslgnors to Schering Corporation, Bloom?eld,
N. J ., a corporation of New Jersey
> No Drawing. Application .Ianuary 31, 1939, Se
rial No. 253,734. In Germany February 2,
9 Claims. (Cl. 260—-397.7)
This invention relates to valuable derivatives
of sulphonamides and a method of making the
convertible thereinto, while X indicates an acyl
residue of a carboxylic acid.
In accordance with the invention by the intro
As particularly valuable therapeutic agents
duction of such an acyl residue into the sulphon- '
amide group the hydrogen atom still present in
streptococcic, staphylococcic, pneumococcic, and
septicemia conditions, have proved compounds
the sulphonamide group becomes replaceable by
metal. By replacement of this hydrogen atom by
of the type of the sulphonamides such as
are described, for example, in German Pat
alkali metal it is possible to convert otherwise
insoluble compounds of the above mentioned class
10 of substances into compounds easily soluble in
water with neutral reaction. By this means the
possibility is provided of employing all the com
pounds according to the invention not only as such
but in the form of their water-soluble salts in
15 aqueous solution and to administer them, for
example, by intravenous or subcutaneous in
jection whereby a more rapid effect is promoted.
In addition there is the fact that the therapeutic‘
activity of these substances is not reduced by the
tents Nos. 607,537, 610,320,. 638,701, French
Patents Nos. 812,053, 820,546, British Patents
Nos. 482,576 and 462,765, Swiss Patents Nos.
192,699 and 192,700, U. S. Patents Nos. 2,111,768
and 2,111,913 and others; compare also the work
of Fourneau, Tréfouel, Nitti and Bovet, Comptes
Rendus Soc. Biol. 1936, vol. 122, pages 258-259;
Tréfouel, Nitti and Bovet, Annales de l’Institut
‘ Pasteur, vol. 58, pages 30-47 (1937); Buttle, Gray
and Stephenson, Lancet of 6.6.36, pages 1286
1290; Mayer, Oechslin, Comptes Rendus, vol. 205, 20
reaction speci?ed but in many ~ cases even in
pages 181-182 (1937); Goissedet, Despois and
Mayer, Comptes Rendus Soc. Biol. 1936, vol. 121,
pages 1082-1084 and others. All these compounds
Even if a few of the already known compounds
contain a sulphonamide group —SO2NH2 con
nected to an aromatic, heterocyclic or aromatic
heterocyclic residue. Very active compounds of
this class of substances contain in p-position to
of the sulphonamide type are capable of forming
water-soluble salts as, for example, the p
the sulphonamide group an amino group or a
group convertible thereinto. As the best known 1'
aminobenzene-sulphonamide hydrochloride, the
salts obtained according to the present invention
are distinguished from these known salts by the
fact that the latter do not pass into solution with ‘
neutral reaction and on this account can find no
compounds of this type may be mentioned the p 30 application for injection purposes.
sulphanilic acid amide NH2.C6H4.SO2NH2 and the
For the manufacture of the compounds ac
azodyestuffs derived therefrom of the type of
cording to the present invention certain types
of reaction may be followed which in themselves
are known to the expert. Essentially two main
groups of methods of production can, be dis
In compounds of this type also the nuclear bound 35 tinguished, namely;
amino groups can be substituted by suitable sub
1. Such in which the residue R.SOzNH-I— is pre
stituents, for example, by acyl- residues, in par
viously formed and the acyl group introduced,
ticular by those containing acid groups, or by
2. Such in which the residue -—NH.X is pre
carboxy-alkyl residues, by carbohydrate residues, 40 viously formed and the residue R.SO2— intro
by benzyl residues and the like. A whole series of
compounds of this type is di?icultly soluble or
To the ?rst mentioned group of methods of
insoluble in water so that the administration
manufacture belongs the simplest method, namely
thereof presents di?iculty.
the acylation methods known per se, for instance,
In accordance with the present invention par 45 by means of acid anhydrides, acyl chlorides,
ticularly valuable derivatives of compounds of this
ketenes and the like. If the residue R of the
type are produced when in them a hydrogen atom
above formula in addition contains an amino
of the sulphonamide group is replaced by an acyl
group, the acylation must naturally be carried 0‘: 1.;
residue. The compounds thus obtained according
in such a manner that together with the acylation
to the iinvention correspond to the following
50 of the amino group the acylation of the sulphon
amide group simultaneously takes place, that is
to say in general an excess of acylating agent will
In this formula R indicates an aromatic, hetero
be employed. 'If necessary then by partial hy
cyclic or aromatic-heterocylic residue containing
drolysis the acyl group of the nuclear bound
at least one nuclear bound amino group or a group 55 amino group may be split off again.
clic nitro compound which contains a nuclear
Obviously also such acylation methods can be
bound basic nitrogen atom can be condensed in
customary manner to the azo compound. It is
also possible to reduce corresponding azoxy com
pounds to the azo compounds or to dehydrogenate
employed in which from the commencement only‘
an acylation of the sulphonamide group takes
place and the nuclear bound amino group remains
unchanged, as, for example, by causing the acyl
correspondingly constituted hydrazo-compounds
ating agent to react on the silver compound of
to the azo compounds.
the sulphonamide.
The formation of the nuclear-bound amino
This group of manufacturing processes includes
' group by splitting of substituents or by conver
also all the processes in which such acylated sul
phonamides are employed as starting materials 10 sion of another group convertible thereinto (ni
tro-, azo-, halogen- and similar groups) is nec
in which the nuclear bound amino group is ?rst
essary in certain instances to render the com
produced after the production of the acylated
pound therapeutically active. Thus, such con
sulphonamide group. It comprises therefore es
version is necessary in the base of the p-halo
sentially two stage processes in which in fact sul
geno-sulfonacylamides, suchas p-chlor- or p
phonamides which contain a group convertible
brombenzenesulfonacetamide, since such com
into the amino group are ?rst acylated whereupon
pounds, as tests have shown, are inactive, and
the nuclear bound amino group is produced.
active compounds are produced therefrom only
The various methods for converting nitrogen
containing and non-nitrogen-containing groups
into an amino group are Well known and are de
scribed, for example, in Houben “Die Methoden
der organischen Chemie,” second edition, 1923
1924, vol. 2, page 315 et seq., vol. 4, page 247 et
seq., page 337 et seq., page 339, et seq., and page
354 et seq. As example may be mentioned the
by conversion into the corresponding p-aminoben
To the second group of manufacturing proc
esses belong all the processes in which such sul
phonic'acids or their derivatives as contain a
nuclear bound amino group or a group convert
ible thereinto, primarily their halides. in partic
acylation of p-nitrobenzene-sulphonamide with
ular the sulphochlorides, are brought into reac
converted into such an acylamino group as can
employed themselves.
tion in the customary manner with the corre
subsequent reduction of the nitro group to the
sponding acid amides in the presence or absence
amino group. Instead of the nitro group also
of condensing agents and/or catalysts and, if nec
any other of the groups convertible into the amino
group can be present, for example, the nitroso, azo, 30 essary, the nuclear bound amino group produced.
Instead of the acid amides it is also possible to
azoxy, hydrazo and the like groups which by
employ, although less preferably, their metal ‘
reduction are converted into the amino group,
compounds, for example, the silver compounds or
halogen, which by treatment with ammonia, suit
the like. It is also possible to cause suitable salts
ably in the presence of catalysts, gives the amino
of the sulphonic acids such as alkali or alkaline
group; the acylamino and azo-methine groups,
earth salts to react with the acid amide, in which
which can be hydrolysed to the amino group, or
case the operation is conducted in the presence of
anacid amide or hydrazide group which can be
such agents as are capable of intermediately form
converted into the amino group by Ho?mann,
ing from the sulphonates anhydrides or chlorides
Curtius or the like degradation reactions, and
others. To this group of manufacturing proc 40 which then enter into reaction with the acid
amide. Such agents are, for example, sulphuryl
esses belongs also the process in which the nu
chloride or the chlorides of the sulphonic acids
clear bound amino group before the acylation is
To this group of manufacturing processes ?
more easily be split off to the amino group than
is the case with the acylated sulphonamide group. 45 nally belongs also the interaction of sulphinic
‘acids or their salts with acid amides which con
Such groups are, for example, the carbomethoxy,
tain a halogen attached to nitrogen.
the carbobenzyloxy group and others as are men
Of course, also other known methods for mak
tioned, for example, in German Patent 556,798.
ing the compounds according to this invention
These can easily by reduction treatment or by
as they are described, for instance, in the above
hydrolysis be split off again without the acylated
mentioned patents or literature references may
sulphonamide group being in?uenced. Also the
be employed. The essential feature of this in
method of benzylating the amine group ‘can be
vention consists, however, in the production of
used with advantage for this type of reaction.
compounds of the general formula R.SO2.NH.X.
To this group of manufacturing processes be
aromatic, heterocyclic or aromatic-heterocyclic
amino-sulphonamide compounds are acylated in
As particularly valuable starting materials for
the reaction of the present invention have proved
the following substances:
the sulphonamide group, and then the free or
p-Aminobenzene-sulphonamide, ,
_ long ?nally also the methods in which at ?rst
again liberated nuclear bound amino group is di
azotized and the diazo compound obtained cou 60 p-Aminobenzene-sulphonamido-benzene-m - sul
pled in the manner known per se, corresponding,
phonamide, and
for example, to the directions of German Patents
p-Amino - benzene - sulphonamido - p - sulphon
Nos. 607,537, 610,320 and others with aromatic,
heterocyclic or aromatic-heterocyclic bases which
their acylamino derivatives or sulphochlo
are capable of coupling. There are obtained in
rides, azo-dyestuffs of the type of the 4-sulphon
this manner azo compounds acylated in the sul
amido-'2'.4’-diamino-1.1’-azobenzene, the glu
phonamide group which on the one hand contain
a nuclearboun-d amino group and on the other
an acylated sulphonamide group and which like
wise constitute valuable therapeutic agents. Ob
viously there can be employed for the manufac
ture of such azo compounds also other manufac
cosides of p-amino-benzene-sulphonamide and
others as are described in the patents and litera
ture references set forth above and in the pend
ing patent applications Ser. No. 147,478 of June
10, 1937, and Ser. No. 210,746 of May 28, 1938.
By interaction of the compounds according to
turing methods known per se as are mentioned in
the invention acylated on the sulphonamide
the above speci?ed patents. Thus, for example,
an aromatic, heterocyclic or aromatic~heterocy 75 group, with metal oxides, hydroxides or carbon
di?icultly in water, linsoluble in benzene and
ates or the like there are obtained the corre
sponding metal'compounds; Thus it is easy to
manufacture the alkali compounds by treating
' 'Exurru: 2
the new compounds with the calculated quantity
of alkali hydroxide solution or sodium carbonate 5
to a neutral reaction and, if necessary, salting out
the alkali salt or precipitating it by the addition
17.2 grams of 4-aminobenzene-sulphonamide
of organic solvents miscible with water. 01'.
are heated to boiling for one hour with 20 cc. of
— course, the salts can be isolated from their solu
propionic acid anhydride. The working up, ac
tions by simply evaporating the latter to dryness. 10 cording to example 1 yields the dipropionyl
It is also possible, however, to produce other
aminobenzene - sulphonamide.
metal compounds, such as the alkaline earth,
from alcohol it forms colorless microscopic
gold, copper, mercury, silver, aluminum, magne
needles of M. P. 232“ C. The product is soluble
sium and the like compounds which are like
in sodium carbonate solution and can be par
wise of practical importance. For the manufac 15 tially saponi?ed by heating with sodium hydroxide
ture of these salts there is especially suitable the
solution as in Example 1, yielding 4-aminoben
known method of double decomposition, accord
zene-sulphon-propionyl-amide of M. P. 130
ing to which, for instance, the alkaline earth
131° C.
metal salts of the acylated sulphonamides (that
is, of alkaline earth metals whose sulphates are 20
insoluble) are reacted with soluble sulphates of
heavy metals. Thereby the insoluble alkaline
21.4 grams of 4-acetylaminobenzene-sulphon~
earth metal sulphate precipitates while the solu
amide are dissolved with 200 cc. of N sodium
ble heavy metal salt of the acylated sulphon
hydroxide solution and shaken with 28.2 grams
amide remains in solution and is isolated there 25 of benzoyl chloride until the benzoyl derivative
from. Also organic bases as, for example, alkyla
separates. The latter is ?ltered with suction and
mines, alkanol amines such as ethanolamines,
for puri?cation taken up in dilute sodium car
bonate solution. It is ?ltered and precipitated
pyridine, aniline, 1 - phenyl - 2.3 - dimethyl-4-di
methylamino-S-pyrazolone, quinine and others
are suitable for salt formation.
Both the acylated sulphonamide/ compounds of
with acetic acid. The precipitate is recrystallised
'30 from dilute alcohol. The 4-acetylaminobemene
sulphonbenzoyl-amide forms needles which on
the formula R.SOz.NH.X and also their metal and
heating decompose at 245-246° C. By heating
other derivatives are intended to find application
with sodium hydroxide solution, as in Example 1,
not only as therapeutic agents but also as inter
partial saponi?cation takes place. The 4-amino
mediate products for the manufacture of other 35 benzene-sulphonbenzoyl-amide obtained has the _
pharmaceutical and. technically valuable sub
stances, for example, for the manufacture of
plant protecting agents and the like.
The following examples illustrate the invention
without, however, limiting the same to them:
melting point of 179-186" C.
26.2 grams of 4-benzylaminobenzene-sulphon
17.2 grams of 4-aminobenzene-sulphonami‘de
amide are heated for some hours with 250 cc. of
acetic anhydride. The working up according to
Example 1 yields the 4-benzylaminobenzene
sulphonacetylamide. It is puri?ed by recrystal
are heated to boiling with 75 cc. of acetic anhy
dride for one hour and thereupon the diacetyl
lisation from alcohol and then forms microscopic
needles of melting point of 143-144“ C.
product caused to separate by stirring into ice
water. After recrystallisation from alcohol the 4
acetylaminobenzene-sulphonacetyl - amide forms
colorless prisms of melting point 253° C. with
decomposition. The product is easily soluble in
alkalies and forms neutral salts. The acetylation
can also take place with acetyl chloride. Instead
of the 4-aminobenzene-sulphonamide also 4
acetylaminobenzene-sulphonamide can be em
4.4’- acetylaminobenzene-sulphonamidobenzene
32.7 grams of 4.4’-aminobenzene-sulphon
amidobenzene-sulphonamide are heated to boil-v
ing with 200 cc. of acetic anhydride. ~ After solu
tion has taken place the whole is boiled for a
further hour and then the diacetyl compound
caused to separate by pouring the solution into
ice water. -The precipitate is puri?ed by dissolv
same product.
ing in sodium carbonate solution and precipita
By heating the diacetyl compound with so
dium hydroxide solution partial saponi?cation 60 tion of the ?ltrate with acetic acid. Recrystal
lised from dilute alcohol the product forms color
of the acetyl groups takes place. 25.6 grams of
less needles which melt at 178° C. By partial
diacetyl compound are heated to boiling for some
saponi?cation with normal sodium hydroxide
hours with 100 cc. of 2 N sodium hydroxide solu
solution the corresponding amino product of
tion. The precipitate produced by acidi?cation
ployed. The action of 4-acetylaminobenzene
sulphonic acid chloride on acetamide yields the
of the solution with acetic acid is ?ltered off and 65 M. P. 187° C. is obtained.
treated with dilute sodium carbonate solution.
The 4-aminobenzene-sulphonacetylamide passes
into solution while the simultaneously formed 4
acetylaminobenzene=sulphonamide remains un
dissolved. It is ?ltered with suction and the ?l 70 32.7 grams of 4-aminobenzene-sulphonamido
B-benzene-sulphonamide of M. P. 156° C. (pro- trate again acidi?ed with acetic acid. The 4
aminobenzene-sulphonacetamide separates out
duced by the action of 4-acetylaminobenzene
and is recrystallised from water. It forms color
sulphonic acid chloride on 3-aminobenzene-sul
phonamide and subsequent saponi?cation of the
less lustrous rhombic crystals of M. P. 181° C. It
is easily soluble in alcohol and acetone, more 75 acetyl group of the condensation product) are
and then introduced into ice water. The precipi
tated carbethoxy-sulphanilic acid chloride is for
puri?cation dissolved in cold methyl alcohol~ and
heated with 200 cc. of acetic anhydride for one
hour to boiling and thereupon the diacetyl product
isolated as described in ‘Example 5. After recrys
tallisation from dilute alcohol the product melts
precipitated again by the addition of water. The
at 145-146°. By partial saponi?cation the corre
sponding amino compound is obtained.
melting point is 104-105“ C. By introduction of
ammonia into the ethereal solution of the car
bethoxy-sulphanilic acid chloride there is pro
duced in good yield the 4-carbethoxy-sulphanilic
acid amide of melting point of 238° C.
244 grams of 4-carbethoxy-aminobenzene-sul
phonamde, 1.25 litres of glacial acetic acid and
21.4 grams of 4-aminobenzene-sulphonacet
80 grams of acetyl chloride are heated to boil
amide are diazotised in hydrochloric acid solution
with 6.9 grams of sodium nitrite and the cold - ing for 2 hours. The acetylatedv product is intro
duced into water, ?ltered with suction and repre
diazonium chloride solution treated with a hydro
chloric acid solution of 11 grams of m-phenylene 15 cipitated. It melts .after recrystallization irom
dilute acetone at 244° C.
diamine. The coupling product immediately
For splitting o?.’ the carbethoxy group the
separates as a dark red precipitate. It is ?ltered
4 - carbethoxy amino - benzene - sulphonacetyl
with suction, taken up with dilute sodium car
amide is dissolved in seven times the quantity oil
bonate solution, ?ltered and acidi?ed in the hot
with acetic acid. The dyestu? separates in the 20 2 N sodium hydroxide solution and the solution
heated for 10 minutes to 80° C. By acidi?cation
form of blue-red leaflets of‘ metallic lustre. On
with acetic acid the 4-aminobenzene-sulphon
heating decomposition takes place at 180° C.
acetylamide is precipitated and is puri?ed by
The same product is obtained when the » 4
recrystallisation from water. Melting point 181°
sulphonamido - 2'.4'- diamino-l.1’-azobenzene is
acetylated and partially saponi?ed. The dyestu? 25 C. The yields according to this process corre
spond to those given imijxample 8.
Instead of 4-carbethoxy-aminobenzene-sul
is easily soluble in dilute sodium, carbonate solu
phonamide there can also be employed as start
Exmrta 8
ing material the carbomethoxy compound; it is
30 obtained in the following manner:
82.3 grams of the sodium salt or carbometh
172 grams oi’ sulphanilic acid amide are dis
solved in 2000 cc. of N sodium hydroxide solution
oxy-sulphanilic acid (Niilting, Berichte 21, 3155)
4-N-carbonic acid benzyl ester. aminobenzene
tion and washed _i’ree from acid. The amide is
are ground with 70 grams oi! phosphorus penta
and to the solution at 0°.C. with stirring and
chloride. The solid mass is introduced into ice
cooling 340 grams of benzyl-chlbrocarbonic acid
ester added. After several hours the precipitated 35 water, the undissolved portions ?ltered with suc
sulphonamide is separated, washed with dilute
hydrochloric acid and water and recrystallised
from methyl alcohol. Melting point 192-192.5°
‘C. The yield amounts to 250 grams.
By one hour's boiling of this product with ?ve
. times the quantity of acetic anhydride and pour
21.4 grams of 4-aminobenzene-sulphonacet
amide are heated to boiling with 17.1 grams of
glucose and 200 cos. of absolute ethyl alcohol
' until a clear solution is produced.
From the
solution on long standing the glucose compound
ciystallises in colorless needles. The crystals are
separated and recrystallised from absolute ethyl
The --4-N-carbonic acid benzylr ester aminoben
zene-sulphonacetylamide melts after recrystal
' lisation'from methyl alcohol at 167-168° C. The
yield amounts to 200 grams. r
ilic acid amide melts at 226-227" C.
ing or the solution into water the-acetyl derivative
is precipitated. It is ?ltered with suction, taken
up in dilute sodium‘ carbonate solution. ?ltered
from any unchanged starting material and in the
?ltrate precipitated again by hydrochloric acid.‘
obtained by introduction of ammonia'into the
ethereal solution of the sulphochloride (melting
point 117-118“ C.) The carbomethoxy-sulphan
alcohol. The melting point is 191° C. The com
pound is easily soluble in water, more dimcultly
in ethyl alcohol. The alkali salts are easily solu
ble in water with neutral reaction.
To split off the carbobenzyloxy group, 200
grams of the 4-N-carbonic acid benzyl ester ami
nobenzene-sulphonacetylamide are dissolved in
3 litres of alcohol and with the addition oi.’ 5
grams of'palladium black shaken with hydrogen
so long as the latter is still taken up. 'For this
purpose 7.6 litres of hydrogen are employed.
Into a solution of 21.4 grams of 4-amino-ben
The solution is ?ltered oil from catalyst, concenzene-sulphonacetamide in 200 cc. of 2 N sodium
trated and the residue recrystallised from water. 60 hydroxide solution is introduced at 50° C. a strong
The yield amounts to 106 grams of 4-amino
stream of phosgene. When the reaction is com
benzene-sulphonacetylamide of melting point of
plete the precipitate produced is ?ltered with
181° C. The same _ld is obtained when the
suction and for puri?cation precipitated from an
catalytic hydrogenat'on is carried out in aque
alkaline solution in the hot with acetic acid. The
65 product forms colorless microscopic needles
ous alkaline instead of in alcoholic solution.
The splitting off of the benzyl-carbonic acid
residue can also “take place by several hours
treatment with three times the molar quantity
of normal sodium hydroxide solution. at 60° C.
which decompose at 255° C. The yield is quanti
tative. The product is very di?lcultly soluble in
organic solvents. The water-solubility of its
alkali salts is considerable.
' Exmrnn 9
40 grams oi.’ carbanilic acid ethyl ester (Hente
schel, Berichte vol. 18, page 978) are,‘ introduced '1
24.4 grams of 4-carbethoxy-sulphanilic acid
at 0° C. into 160 grams of chlorsulphonic acid.
The mixture is heated for an. hour to 55-60° C. 76 amide are dissolved in 250 cc. 0! pyridine and
with stirring and cooling 14.2 grams of nicotinic
acid chloride introduced drop by drop. The clear
solution is introduced into ice water and treated
with hydrochloric acid to an acid reaction to
Congo red. The precipitate is isolated and re
crystallised irom dilute alcohol.
and the ?ltrate is precipitated with hydrochloric
acid. The precipitate consists of 4-benzylamino
benzene-sulphonacetamide which 'on recrystalli
sation from alcohol melts at 143-144° C. The
yield amounts to 15 grams.
4-acetylsulphamidophenyl-azo-I ’ (naphthal
The product
forms needles of M. P. 241° C.
For saponi?cation of the carbethoxy‘ group 30
6'.8'-disulphonic acid)
grams of 4-carbethoxyaminobenzene-sulphon
nicotoylamide are allowed to stand for 24 hours 10
21.4 grams of 4-aminobenzene-su1phon-acetyl- '
in 210 cc. of 2 N sodium hydroxide solution. The
amide obtained, for instance, according to Ex
solution is then acidi?ed with acetic acid, the
ample 1 are diazotized and in sodium carbonate
precipitate ?ltered with suction washed with
solution coupled with a solution of 35 grams of
water and recrystallised from dilute alcohol.
2-naphthol-6.8-disulphonic acid sodium salt. In
The 4 - aminobenzene - sulphon - nicotoylamide
order to isolate the reaction product ‘the solution
forms colorless needles and melts at 246° C. '
is slightly acidi?ed and the dyestuff is salted
out by addition of sodium chloride. The disodi
um salt obtained thereby is recrystallised from
dilute alcohol and forms vermillion-reddish col_
24.5 grams of 4-carbethoxysulphanilic acid 20 ored prismatic needles which decompose on heat
amide and 150 cc. of butyric acid anhydride are
ing at 333°C.
stirred into water after heating for 1 hour.
Thereby the acylated product precipitates in the
form of an oil. By recrystallisation of the solidi
24.5 grams of 4-carbethoxy-aminobenzene
?ed oil from dilute alcohol the 4-carbethoXy 25
sulphon-amide are heated with 150 cc. of pro
aminobenzene-sulphon-butyryl-amide is ob
pionic acid anhydride for one hour to boiling.
tained in the form of needles of melting point
On stirring the mass into ice-water an oil pre
cipitates that soon solidi?es. After recrystallisa
The saponi?cation is carried out as described
above by treatment with 2 N sodium hydroxide 30 tion the 4-carbethoxy-aminobenzene-sulphon
propionyl-amide is obtained in the form of
solution. The 4-aminobenzene-sulphonbutyryl
needles having a melting point of 208° IC. The
amide obtained thereby yields on recrystallisa
yield amounts to 24 grams.
tion from alcohol a product having a melting
The saponi?cation of the carbethoxy residue
point of 125°.
24.5 grams of .4-carbethoXy-sulphanilio acid
35 is carried out in the same manner as described
in Example 9, i. e. by heating with 2 N sodium
hydroxide solution. The 4-aminobenzene-sul~
obtained ‘therefrom by
amide are heated for 2 hours to 145° C. with
acidifying with acetic acid solidi?es after a short
125 grams of crotonic acid and 11 grams of 40 time and forms crystals that on recrystallisation
crotonic acid chloride. After cooling the reac
from dilute alcohol melt at 130-131“ C.
tion mixture is stirred into 2 liters of water.
The undissolved portion is separated, taken up
in sodium carbonate solution and precipitated
after ?ltration with acetic acid. The crotonylic
24.4 grams of 4-carbethoXy-sulphanilic acid
derivative redissolved from alcohol melts at
224° C.
amide are heated with 16 grams of phenacetyl
chloride for several hours to 160-170° C._ The
Saponi?cation yields the 4-aminobenzene
cooled reaction mixture is dissolved in dilute
sodium carbonate solution and is acidi?ed after
sulphoncrotonyl-amide which on recrystallisa
tion from water melts at 175° C.
?ltration, with hydrochloric acid. The 4-car
bethoxy-sulphanilic acid phenacetyl amide pref
cipitated thereby is recrystallised from alcohol
and melts at 209° C.
The saponi?cation of this compound is carried
out by treating the same with 2 N sodium hy
droXide solution. The 4-aminobenzene-sulphon
21.4 grams of 4-acetylaminobenzene-sulphon
‘ amide are dissolved in 200 cc. N sodium hy
droxide solution and are shaken with 18.6 grams
of 4-nitrobenzoy1 chloride for several hours. The
phenacetyl-amide obtained thereby melts after
?ltered solution is‘ acidi?ed, the precipitate is
dissolved in sodium carbonate solution, again 60
?ltered, and the ?ltrate precipitated by means
of acid. On recrystallisation from alcohol the
4-acetylaminobenzene-sulphon-p - nitrobenzoyl
amide of M. P. 256° C. is obtained.
4-benzyZaminobenzene-sulphon-acetyl-amide -
21.4 grams of 4-aminobenzene-sulphon-acet
ylamide obtained, for instance, according to EX
ample 1 and having a melting point of 181° C.
are heated with 12.6 grams of benzylchloride, 24
grams of calcium carbonate, and 500 cc. of water
for several hours while stirring, to boiling. After
adding 6 grams of sodium carbonate the mix
ture is again heated to boiling, ?ltered while hot,
recrystallisation'from dilute alcohol at 182° C.
acetic acid amide
24.4 grams ‘of 4-carbethoxy-sulphanilic acid
amide and 50 grams of chloro acetic acid anhy
dride are heated for one hour to 120-125° C. The
reaction mixture is then triturated with water,
the undissolved is removed by ?ltration, and is
recrystallised from dilute alcohol. It melts at
229° C. The 4-carbethoxy-aminobenzene-sul
phon-chloro-acetic acid amide yields on treat
ment with concentrated ammonia solution at
ordinary room temperature 4-carbethoxy-amino
benzene-sulphonamino-acetic acid amide which
75 on_ recrystallisation from water melts at 223° C.
Exmem 21
chloride and the mixture is heated for one hour
to ‘190° C. The pulverised reaction mixture is
dissolved in dilute sodium carbonate solution,
?ltered, the ?ltrate acidi?ed by means of hydro
4-,‘aminobenzene-sulphonsalicyltc acid amide
24.4 grams ' of 4-carbethoxy-sulphanilic acid
amide and 15.7 grams of salicylic acid chloride
chloric acid, the precipitate ?ltered off by suction,
and recrystallised from dilute alcohol. The di
carbethoxy compound melts at 201° C. By treat
are heated for several hours to 170-180° C. The
reaction mixture is then dissolved in dilute sodium
carbonate solution. The solution is ?ltered and
ing the same with 2 N sodium hydroxide solution
precipitated with hydrochloric acid. By recrys
the two carbethoxy groups are split off and the
tallisation from glacial acetic acid the reaction 10 4.4’-diamino-diphenyl-disulphon-mucic acid di
product is obtained in a pure state and melting at
amide having a melting point of 233° C. is ob
242° C. The saponi?cation with 2 N sodium hy
droxide solution yields 4-aminobenzene-sulphon
salicylic acid amide which on recrystallisation
from water melts at 200-201° C.
24.4 grams of 4-carbethoxy-sulphanilic acid
4-aminobenzene-sulphonfuroyl amide
48.8 grams of 4-carbethoxy-sulphanilic acid
amide are dissolved in 250 cc. of pyridine and
-mixed while cooling and stirring, slowly and
gradually with 26.5 grams of pyromucic acid chlo
ride. After standing for some time the solution
is poured into ice-water, ?ltered and the con
densation product precipitated by acidifying with
amide are dissolved in 250 cc. of pyridine.
4-aminobenzene-sulphonfuroyl-amide is obtained
on acidi?cation. It forms a crystalline mass that
this solution there are added drop by drop while
stirring 11 grams of chloro carbonic acid ethyl
20 ester. The solution is. heated for several hours
to 60-'70° C., then diluted with 5 times its amount
of water and acidi?ed with hydrochloric acid.
The precipitate obtained is dissolved in dilute so
dium carbonate solution in order to remove any
25 non-reacted starting material, the solution is ?l
hydrochloric acid. The product purified by re
precipitation, melts at 259° C., with decomposi
tion. The yield is almost quantitative. By treat
ing this product with 2 N sodium hydroxide solu
tion the carbethoxy group is split off and the 30
ExAmPLz 26
tered, and the 4-carbethoxy-aminobenzene-sul
phon-carbethoxy-amide is precipitated from the
?ltrate by means of hydrochloric acid. On re
crystallisation from alcohol needles having a
melting point of 162° C. are obtained.
By treating this product with 2 N sodium hy
droxide solution the carbethoxy group is split 01!
on recrystallisation from water melts at 188
from the nuclear amido group. The 4-aminoben
189° c.
zene-sulphoncarbethoxy-amide obtained thereby
ExAmLn 23
35 melts after recrystallisation from alcohol at 133°
C. It forms alkali salts that are readily soluble
in water with neutral reaction. »
Instead of reacting 4-carbethoxy-sulphanllic
24.4 grams of 4-carbethoxy-sulphanilic acid
acid amide with- one mol chloro carbonic acid
amide are slowly heated with ‘29.6 grams of hydno 40 ester one may proceed in such a manner that one
chaulic (chaulmoogric) acid chloride (Wagner
mol of sulphanilic acid amide is reacted with 2
Jauregg und Voigt, Berichte der Deutschen Chem
mols of chloro carbonic acid ester, thereby yield
ischen Gesellschaft, vol. 71, page 1975) to 148° C.
ing the same dicarbethoxy-sulphanilic acid
The reaction product is poured into water and is
brought into solution with an amount of sodium
carbonate su?icient to dissolve the product. After
?ltration hydrochloric acid is added and the pre
cipitate is recrystallised from dilute alcohol in
the presence of charcoal. The product forms
26.4 grams of 4-carbethoxy-sulphanilic' acid
colorless globular crystals having a melting point 50 chloride are heated with 100 grams of urethane
‘of 131° C.
to 140-150° C. until a sample is readily and com
pletely soluble in dilute sodium carbonate solu
tion. The reaction mixture is then dissolved in
4.4’-diaminodiphenyl-disulphonadipic acid
very dilute sodium carbonate solution, ?ltered.
and the, ?ltrate acidi?ed with acetic acid. The
48.8 grams of 4-carbethoxy-sulphanilic acid
precipitate is recrystallised from alcohol and cor
amide are heated with 18.3 grams of adipic acid
responds with the product obtained according to
dichloride for several hours to 150° C. The solid
the preceding example.
mass is broken into pieces and is dissolved with
sodium carbonate solution. After acidifying the
?ltered solution, the precipitate is recrystallised
from a large quantity of dilute alcohol. The
product melts at 229° C. with decomposition. The
splitting off of the carbethoxy group is carried out
in customary manner by means of 2 N sodium
hydroxide solution. Thereby the 4.4'-diamino
diphenyl-disulphon-adipic acid diamide is ob
tained that after decrystallisation from dilute
alcohol melts at 212° C.
Salts of 4-aminobenzene-sulphon-acetamide
(a) Sodium salt: 21.4 grams of 4-aminoben
zene-sulphon-acetamideare dissolved in 100 cc.
of N sodium hydroxide solution and the sodium
salt is precipitated with alcohol after concentrat
ing the solution. On recrystallisation from dilute
alcohol the salt melts at 257° C.
(b) Barium salt: 21.4 grams of 4-aminoben
zene-sulphon-acetamide are dissolved in an aque
4.4’-diamin0-diphenyl-disulphon-mucic acid
48.8 grams of 4-carbethoxy-sulphaniiie acid
amide are mixed with 24.7 grams of music acid
ous solution of 15.8 grams of barium hydroxide,
the solution is evaporated to dryness and the‘resi
due is recrystallised from dilute alcohol. Melt
ing point: 185° C. (with decomposition).
(c) Copper salt: The aqueous solution of 5
grams of the barium salt of 4-aminobenzene-sul
14 -
phon-acetamide is mixed with 2.2 grams of copper
sulphate. The ?ltrated solution is evaporated to
A greenish powder is obtained.
Exams 31
sodium salt
(d) Ammonium salt: 4-ami‘nobenzene-rsul
phon-acetamide is dissolved in aqueous ammonia
solution to neutral reaction and evaporated to
dryness, A crystalline powder is obtained which
on recrystallisation from alcohol melts at 156° C.
with decomposition.
(e) Pyridine salt: 4-aminobenzene-sulphon
acetamide is dissolved while heating in pyridine.
The pyridine salt precipitated on cooling is re
crystallised from alcohol. It has a melting point
27.7 grams of‘ 4-aminobenzene-sulphon-nico
toyl-amide are dissolved in 100 cc. of N sodium
hydroxide solution. The solution is evaporated
to dryness. The residue is recrystallised from di
lute alcohol and gives a product that on heating
decomposes beginning at 270° C. whereby color
ation takes place.
Exlunmr: s2
' of 120° C.
(f) Diethanol amine salt: 21.4 grams of 4-ami 15
nobenzene-sulphon-acetamide are brought into
solution by means of 10.5 grams of diethanol
amine in 100 cc. of water. The residue obtained
on evaporating the solution to dryness is recrys
coside-magnesium salt
37.6 grams of 4-aminobenzene-sulphon-acet
amide glucoside are dissolved in 150 cc. of water
and boiled with 4.2 grams of magnesium carbon
ate. After evaporated to dryness the filtered so
tallised from dilute alcohol. Melting point of the 20 lution, the residue is recrystallised from dilute
alcohol and yields a'salt melting at about 165
salt: 155° C. (not sharp).
167" C.
(9) Calcium salt: 21.4 grams of 4-aminoben
Examine 33
zene-sulphon-acetamide are dissolved in 100 cc.
of water while heating. To this solution there
4.4'- aminobenzene - sulphon - amidobenzene are added 5.0 g. of calcium carbonate. After 25
sulphon-acetamide sodium salt
boiling for a short time it is ?ltered and the ill
of 4.4'-aminobenzene-sulphon
trate evaporated to dryness. Thevresidue is re
amidobenzene-sulphon-acetamide are dissolved
crystallised from dilute alcohol.
in 100 cc. of water and 100 cc. of N- sodium hy
(h) Silver salt: The aqueous solution 'of_ 4-ami
nobenzene-sulphon-acetamide sodium is mixed 30 droxide solution. From the concentrated solu
tion alcohol precipitates the sodium salt in crys
. with a silver nitrate solution. The silver salt pre
cipitates, is ?ltered off by suction, and is washed
with water, alcohol, and ether. The product has
a melting point of 216° C.
talline form.
calcium salt
(i) Mercury salt: From an aqueous solution of 35
the sodium salt of 4-aminobenzene-sulphon-acet
30.4 grams _ of 4-benzylaminobenzene-sulphon
amide the mercury salt of this sulphon amide
acetamide are heated with 200cc. of water and
compound is obtained by precipitation by means
5 grams of calcium carbonate for several hours to
of a mercury acetate solution. It has a melting
point of 251° C. (under decomposition).
The ?ltrate is concentrated by evaporation and
(k) Quinine salt: 31.4 grams of 4-aminoben
the syrupy residue is triturated with absolute
zene-sulphon-acetamide and 32.4 grams of qui
alcohol whereby the calcium salt separates in
nine are dissolved in 200 cc. of alcohol. After
crystalline form having a melting point of 268°
distilling off the alcohol the quinine salt remains.
C. (thereby decomposing).
It is soluble in water and melts at about 73° C.
(l) Morphine salt: 21.4 grams of 4-aminoben
zene-sulphon-acetamide and 30.3 grams of mor
4-acety'l-sulphamido-2'.4'-dia1nido-1 .1 ' -azo
phine are dissolved while heating in 200 cc. of al
benzene-sodium salt
cohol. The salt is precipitated by adding ether
33.3 grams of 4-acetyl-sulphamido-2'.4'-dia
and has a melting point of 160° C. (not sharp).
calcium salt
22.8 grams of 4-aminobenzene-sulphonpropi
onyl amide are dissolved while heating in 150 cc.
of water. To this solution 5.0 grams of calcium
carbonate are added. After heating to boiling
the solution is ?ltered and the ?ltrate is evapo
rated to dryness. The residue is recrystallised
from dilute alcohol and has a melting point of
283° C. (with decomposition).
mldo-1.1’-azobenzene are dissolved in 200 cc. of
water and 100 cc. of N sodium hydroxide solu
tion while heating. On addition of alcohol and
ether the sodium salt crystallises from the solu
tion in orange-brown needles of melting point of
55 207° C. (thereby decomposing).
10 grams of 2-aminopyridine-5-sulfonamide
60 obtained
from 2-chloropyridine-5-sulfonamide
by reaction with concentrated aqueous ammonia
solution at 150° C. in a closed container under
pressure, are heated with 100 cc. of acetic acid
anhydride for 1 hour to boiling; after cooling the
65 solution is poured into about 1 liter of water while
4-aminobenzene-sulphonfuroyl-amide mag
nesium salt
stirring, the precipitate obtained ?ltered of! by
suction and recrystallized from water while add
ing animal charcoal. The 2-acetyl-aminopyri
dine-5-sulfonacetamide (melting point 278-79°
26.6 grams of 4-aminobenzene-sulphonfuroyl 70 C.) is soluble in sodium carbonate solution and
amide are dissolved while heating in 200 cc. of
insoluble in acids. It can be transformed by par
water. The solution is heated to boiling with 4.2
tial saponi?cation into the 2-aminopyridine-5
grams of magnesium carbonate. The ?ltered so-.
lution is concentrated by evaporation and is re
In‘ the same manner there is obtained on acet
crystallised from dilute alcohol.
75 ylatlon of 2-anilidopyridine-5-sulionamide or
8. N'-acylsulfanilamidesbof the following for
melting point 178° 0., produced from z-chloro
pyridine-5-sulfonamide by boiling with aniline,
the 2-anilldo-pyridine-5-sulfonacetamide.
Exaurm 3'7
4. 4-amino-benzene-sulfanacetylamide.
5. The sodium salt of 4-amino-benzene-sul
6. In a process for the manufacture of Nl-acyl
5 grams of 4-aminobenzene sulfonacetamide 10 sulphonamides, the step comprising subjecting a
are diazotized in a customary manner in hydro
sulphonamide compound having directly attached
chloric acid solution with 1.6 grams of sodium
the sulphur atom a ring carbon of an aromatic'
nitrite. To the diazo solution there is added a
residue which has an amino group linked through
hydrochloric acid solution of 2.6 grams of 2.6-di
the nitrogen to a ring carbon in p-position to the
aminopyrid'ine. After adding sodium acetate to
this solution a voluminous, orange-reddish pre— 15 first-mentioned carbon, to the action of at least 2
mols of an acylating agent to acylate both the
cipitate of the reaction product is formed which
amidic nitrogen and the nuclearly bound amino
group, the sulfonamide group being converted
is ?ltered off by suction, washed with water and
recrystallized from alcohol. The azo compound
forms orange-reddish needles of melting point,
191-192? C. and is soluble in sodium carbonate
Instead of pyridine compounds other hetero
cyclic compounds may be used likewise such as
into the group -—SO2.NH.OC.R, the group —OC.R
being the acyl radical of a carboxylic acid.
7. In a process for the manufacture of NL-acyl
sulphonamides, the steps comprising subjecting
a sulphonamide compound having directly at
tached to the sulphur atom a ring carbon of an
‘ those of the quinoline, pyrrol, indol, pyrazol and
25 aromatic residue which has an amino group
the like series.
linked through the nitrogen to a ring carbon in
p-position to the ?rst-mentioned carbon, to the
action of at least 2 mols of an acylating agent to
ployed, for example, the anhydrides or halides of
acylate both the amidic nitrogen and the nu
higher fatty acids such as those of palmitic acid,
hydnocarpus acid, phenyl-cinchoninic acid, Pyri 30 clearly bound amino group, the sulfonamide
group being converted into the group
dine carboxylic acids and others.
It is true that sulphonamides amino substituted
in the nucleus have previously been acylated,
compare French'speci?cation 820,546. As, how
the group —0'C.R. being the acyl radical of a
ever, is shown by the more detailed description 35 carboxylic acid, and partially hydrolyzing the
acylated product to regenerate only the nuclear
of the speci?cation in this case always 1 mol of
amino group.
acylating agent is employed for 1 mol of the sul
8. Process for the manufacture of 4-amino
phonamide. By this means, however, only the
benzenesulphonacylamides, comprising subject
nuclear bound amino .group is acylated. Accord
ing p-aminobenzenesulpho'namide to the action
ing to the process of the present application,
of at least 2 mols of an acylating agent to‘ acylate
however, an excess of acylating agent is employed
both the amidic nitrogen and the nuclearly bound
so that both the nuclear bound amino group and
amino group, the sulphonamide group being con
also the sulphonamide group are acylated; one
verted into the group —SO2.NH.OC.R, the group
of these acyl groups and in fact that which has
--OC.R being the acyl radical of a carboxylic
entered the nuclear bound amino group can then
acid, and saponifying the 4-acylamino group to . .5 4
again easily be split off so that the free amino
Instead of the acylating agents employed in
these examples obviously also others can be em
group is reformed.
yield the 4-aminobenzenesulphonacylamide. '
9. In a process for the manufacture of Nl-acyl
In the subjoined claims the term "aromatic”
is to be understood as embracing compounds hav
sulphonamides, the steps comprising subjecting
ing either a phenyl or a pyridyl radical, e. g. the 50 a sulphonamide compound having directly at
tached to the sulphur atom a ring carbon of an
aromatic residue which has an amino group
linked through the nitrogen to a ring'carbon in
What we claim is:
p-position to the ?rst-mentioned carbon, to the
1. A 4-aminobenzene-sulfonacetylamide of the
55 action of at least 2 mols of an acylating agent
general formula
to acylate both the amidic nitrogen and the
nuclearly bound amino‘ group, the sulfonamide
benzene, pyridine and quinoline compounds dis
closed hereinabove.
group being converted into the group
wherein Y is a member of the group consisting
‘of hydrogen and metals.
2. A process for preparing N'-acylsulfanil
amides which comprises reacting sulfanilamide
the group —-OC.R being the acyl radical of a car
boxylic acid, and converting the Nl-acyl sul
with at least two equivalents or a member of ' ' yphonamide’s into salts by treatment with a mem
thegroup consisting of monoliasic aliphatic car
boxylic acid halides arid anhydrides, and hy
drolysing the N4-acylamino group only of the
resulting product.
her" of the group consisting of organic and in
65 ’o'ig'anic bases.
- '
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