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Pat'ented Jan. 7, 1947
Lucas P. Kyrides, St. Louis, Mo., .assignor to
Monsanto Chemical Company, St. Louis, Mo., a
corporation -.of Delaware
No Drawing. "Original application March 20,
1943, Serial No. 479,915. Divided and this .ap
plication October 3, 1945, Serial No. 620,158
other of the anhydridesin the group 'hereinbefore
described or any other suitable anhydride, for
example, acetic anhydride. .Also, the order of
process of producing them.
the substitution .may be reversed, for example,
This application is a division of my co-pend
?rstreactingace'tic anhydride and then reacting
ing application, Serial Number 479,915, ?led
one of ‘the .anhydrides Lin 'thegroup hereinbefore
March .20., 1943.
These new products have been found to pos
The 4,4'-'diaminodip‘heny1 sulfone is desirably
sess therapeuticactivity in the treatment of vari
obtained by re?uxing a mixture of parachloro
ous diseases.
These new derivatives maybe represented by 10 nitrobenzene and sodium sul?de in water, react
ing the resulting \p-aminothiopheno'late with a
the-following generalformula:
This invention relates to certain new deriva
tives of 4,4’-diaminodiphenyl sulfone and to the
molecular equivalent of._parachloronitrobenzene,
acylating the resulting 4-nitro-4'-aminodiphenyl
sul?de with acetic anhydride, oxidizing the sul~
15 ?de to the sulfone, removing the acetyl residue
by acid hydrolysis and reducing the 4-nitrou4’
aminodiphenyl sulfone ‘to thediamino compound.
A desirable procedure ‘for ‘obtaining ‘the mono~
‘acylamino derivatives ‘of ‘the :present ‘invention
20 'comprisesacylatin‘g 4-,nitro-4'-aminodiphenyl su1~
sulfone or oxygen residue.
?dewith va‘m'olecular equivalent of .theanhydride
In preparing these new products, the procedure
of ~one "of the vacids ‘selected "from ‘the group ‘here
in general is the following:
in which X represents a sul?de, disul?de, thionyl,
To a solution (or suspension) of one molecular
‘inbefore ' described, oxidizing‘ the 4-nitro-4’ -acyl
aminodiphenyl sul?de to the 'sulfone and subse
equivalent of 4,4'-diaminodiphenyl sulfone in a
suitablevsolvent, such as acetone, methyl alcohol, 25 quently reducing then'itro re'sidue'to'the amine.
A desirable procedure 'for obtaining the diacyl
ethyl alcohol, ethylene glycol or-dioxane, is added
‘amino derivative of the present invention com
two molecular equivalents of the 'anhydride halide
prises reducing 4;nitro-'4’-aminodiphenyl ‘sul?de
or mono-ester acyl halide of an acid selected from
to‘ 4,4’~diaminodiphenylsul?de, acylating the sul
the group consisting of diglycolic acid, thiodigly
?de with two molecular equivalents of the anhy
colic acid, dithiodiglycolic acid, thionyl ‘diglycolic
~ dride ‘of one of "the acids selected from the group
and sulfondiacetic acids. Thereactio-n mixture is
desirably re?uxed for several hours and the sol
hereinbefore ‘described, ‘and subsequently oxidiz
ing the ‘sul?de to the. sulfone.
vent thereupon Jremoved by evaporation under
‘ Both the free acids 'and‘the salts of the com
reduced pressure. The residue'and oil are solidi
pounds of thepresent’invention may be employed
?ed by treatment with water. The solid material
‘for therapeutic'purposes. Examples of the valkali
is ?ltered on and ‘dried. The product may be
metal~saltsare thesodium and potassium salts of
puri?ed by dissolution in alcohol, ?ltration
vN-'acetyl-N’wliglycolyl-llyl’-diarnirrodipl'lenyl sul
through charcoal, addition of water and agita
fone. These salts maybe prepared, for example,
tion until crystallization of the product is effected.
by dissolving a molecular equivalent of the deriva
Prepared in this manner, the product may retain
tive in an aqueous solution of sodium carbonate
some Water of crystallization, ‘which "maybe re
containing‘ from oneitotwo molecular equivalents
moved if desired by drying the product,.for ex
ample, in a ‘stream of ‘heated'air 'or'in vacuo-at a
temperature : below :the 'decomp osition point -, of the
of the alkali-metal carbonate and recovering the
salt by evaporationof the water. Examples of
45 the alkaline-earth metal salts are the calcium and
magnesium salts. The ammonium salts and sub
stituted ammonium salts may also be employed
for therapeutic purposes, and also the mixed am
dride, halide or ‘mono-ester acyl halide is em
monium and'alkali metal oralkaline-earth metal
ployed in placeof two molecularequivalentsh As
an alternative ‘to the diacylamino compounds, 50 salts. ‘In the therapeuticadministration of the
For the preparation of the monoacylaminorde
rivative, one molecular equivalent of the anhy
mixed acylamino compounds may be prepared by
‘derivatives of this invention, the oral method is
?rst reacting one molecularequivalent of one of
desirably employed, although parenteral methods
the anhydrides in the group hereinbeiore de
scribed With the diaminodiphenyl sul'fone and
"then reacting one "molecular equivalent of an
may'be employed. In the ‘case of parenteral ad
min‘strat'ion, the acid "may be ‘dissolved in ‘an
aqueous solution containing the salt-‘forming sub
stance, such as sodium hydroxide, and the solu
tion thus formed may be employed for the treat
re?uxed in alcohol and recovered by precipi
tion with water and filtration. The product may
,be recrystallized from 50% alcohol.
The following preparations and examples serve
to illustrate the general process. It is to be
4,4’-dz'aminodiphenyl sulfone
understood, however, that these examples do not
limit the invention since other methods for pre-'
paring the compounds of this invention‘are con
4-m'tro-4'-aminodiphenyl sul?de
This substance was prepared according to the
method described in J. Am. Chem. Soc., 61, 2763
15 (1939), in which 4,4’-diaminodipheny1 sul?de
and acetic. anhydride were re?uxed and the re
sulting 4,4’-diacetylaminodiphenyl sul?de was
recovered, oxidized to the sulfone with potassium
This substance may be prepared according to
the method described in J. Am. Chem. Soc., 61,
dichromate in the presence of sulfuric acid and
glacial acetic acid, recovered from the reaction
2763 (1939), in which p~chloronitrobenzene is
mixture and the two acetyl radicals hydrolyzed
re?uxed with sodium sul?de in aqueous solution,
01f with the aid of hydrochloric acid. The 4,4’
the resulting ,p-aminothiophenolate is re?uxed
diaminodiphenyl sulfone is thereupon precipi
with a molecular equivalent of p-chloronitroben
tated by adding sodium carbonate and the pre
zene and the reaction mixture subsequently
steam-distilled to remove unchanged p-chloro 25 cipitate is recovered and washed. The product
may be puri?ed by re?uxing with aqueous alco
nitrobenzene. The product is crystallized from
hol and the puri?ed product recovered by add
the nonvolatile portion and recrystallized from
' ing water to the solution,‘ cooling-with ice and
separating the solid product by ?ltration. In the
30 acylation step any suitable anhydride, for exam
4-nitro-4'-aminodiphenyl suljone
ple, succinic anhydride or propionic anhydride,
or the acyl chloride derivatives of succinic or
propionic acids, may be utilized.
Dz‘glycolic anhydride
A solution of 18.7 grams of 4-nitro-4f-amino
diphenyl sul?de, prepared according to the meth
od described ‘under Preparation No. 1, in 510 cc.
of glacial acetic acid and 161 cc. of acetic anhy-'v 40
dride was re?uxedfor two hours to effect acetyl
ation of the'aminogroup. 800 cc. of glacial acetic
acid was'then added and the temperature was
This substance may be prepared according to
adjusted to 90° C. During three hours, 317 cc.
of 30% hydrogen peroxide was added dropwise. 45 the method described in Annalen, 259, 190 (1890),
in which diglycolic acid is re?uxed with acetyl
The temperature was maintained at 90° C. for
chloride, excess acetyl chloride is distilled off and
an additional half hour and the mixture was
cooled and diluted with 2500 cc. of water.
the residue is dissolved in warm chloroform and
crystallized therefrom on cooling.
was ?ltered off and washed with water. This 50
product was mixed with 360 cc. of concentrated
hydrochloric acid, 1080. cc. of water and 300 cc.
of ethyl alcohol. After re?uxing for about ten 7
hours, the mixture was cooled to 30° C., and
neutralized with 50% soda lye. The precipitated 55
material was ?ltered off, washed with water and
dried at 80° C. Upon analysis, the product was
found to be 4-nitro-4='-aminodiphenyl sulfone.
Thriodz'rglycolric anhydride
/0 v
4,4'-diaminodiphenyl sul?de
‘This substance may be prepared according to
the method described in Annalen 273, 68 (1893),
in which dry thiodiglycolic acid and acetyl chlo
ride are heated, excess acetyl chloride is distilled
o?‘ and the residue is dissolved in warm chloro~
form and crystallized therefrom on cooling.
This substance may be prepared according to
the method described in J. Am. Chem. Soc., 61,,
2763 (1939), in which a suspension of 4-nitro-4' 70
aminodiphenyl sul?de is treated simultaneously
with tin turnings and hydrochloric acid to re
duce the nitro group to amino.
After the re
duction, the product. was precipitated from-the
reaction mixture with alkali, ?ltered therefrom,
Dithiodiglycolyl dichloride
‘ i’
Dithiodiglycolic acid maybe prepared accord
ing to the method described in GermanPatent
No. 194,039, in which sodium chloracetate and
'stirr'e'd until the oil was solidi?ed. Theseus-gee;
sodium disul?de are reacted an‘d'the product is
recovered from the reaction mixture‘. In the
terial was ?ltered, washed with water and: dried
preparation or the acyl dichloride, 21.1 grams of
at 80° C.
dithiodiglycolic acid and‘ 23 grams‘ of thionyl
chloride were re?uxed in 50 cc. of ben'z'enefor
threev hours. The liquid reaction mixture was
cc. of glacial acetic acid was prepared and heated
to 90° C. During three hours, 31.’? cc; of 30% hy
A solution of 27.8 grams of this material in 80
drogen‘ peroxide was added dropwise to the solu
decanted from insoluble material and_ distilled
tion. The temperature was maintained at 90°
C. for an additional half hour. Thereafter the
removed. The residue, dithiodiglycolyl dichlo=
ride, maybe puri?ed by conventional methods.’ 10 mixture was cooled and dilutedwitn100 cc. of
water. The precipitatedproduct was ?ltered off,
As an alternative to the dichloride, the mono-'
washed. with water and‘ dried at 80° C. The'prod
ester 'acyl halide, for example, monomethyl di
not of‘ this reaction was ' N-diglycolyl-44nitro‘-4'
thiodiglycolyl chloride, may be prepared and
until the solvent and excess thionyl'chlori'de were
used. The bromides and other halides of dithioe
diglycolic acid may be used. In using the-hal
ides and mono~ester halides in preparing the
compounds of the present invention, it is neces
sary, after the amide has been formed, to hy
drolyze off the remaining halide residue or mono
ester residue in order ‘to obtain the free carboxyl
aminodiphenyl suli'one.
80° C. The total yield was 39.4’ grams ‘(100%) .
A mixture of 39.4 grams of’ N-diglycolyl-4-ni
tro-‘Y-aminodiphenyl sulfone w‘ith‘35f7 grams of
granulated tin in'{250~ccr of‘ alcohol was ‘treated
with 250 'cc: of '10%"hy'drochloric'acid. The mix;
ture wasstirred'forv'four hours at>40°-45° C., ?l
tered, and the tin' was removed from the ?ltrate
by treatment with hydrogen sul?de. Excess 'hy
(London), 93, 1834, in which thiodiglycolic acid
is treated with an excess of hydrogen'peroxide
drogen sul?de was dissipated by means of ‘a stream
of air or by placing the’ solution under vacuum.
and theproduct is recovered from the reaction
mixture. The anhydride may be prepared ac
cording to the methods described in Preparations
The solution was alkalinized with sodium bicar
bonate, evaporated to dryness under reduced
pressure ‘and the residue was recrystallized. The
product was N-'diglycolyl-4,4='-diaminodiphenyl
Nos. 5 and 6.
Sulfondiacetz'c anhydride
The nitro compound also can~be reduced cata
lytically with’hydrogen, using a" hydrogenation
treated with 100 ‘cc. of water and the mixture was
. stirred until the product solidi?ed. The crystals
were ?ltered off, washed with water-‘and dried at
Thionyldiglycolic acid may be prepared ac
cording to the method described in J. Chem. Soc.
tone?ltraté was evaporated,v the'residual oil was
acetone and-dried; weight 32 grams.v _The ace
25° C. Upon standing, a yellow’ solid” crystallized
out. The productwas ?ltered off, washed with
Thz‘onyldiglycolic anhydride
As‘ an' alternative preparation of N-diglycolyl
ill-nitro’4’-aminodiphenyl" sulfone, a mixture‘of
27.8‘ grams of 4§nitro-4'-aminodiphenyl sulfone,
750g‘; of a‘cetoneiand‘ 12.0 grams of diglycolic ‘an:
hydride was‘ re?uxed for’ twohuors and cooled‘ to
Nahiodigzycdzy'l-rn'ididmmodiphenyz sulfone
Sulfondiacetic acid may be prepared according
to the method described in Berichte 17, 2818, in
which thiodiglycolic acid in aqueous alkaline car.
bonate solution is oxidized with potassium per
manganate and the product is recovered fromv
the reaction mixture. The anhydride may be
prepared according to the methods in Prepara
A mixture‘ of ? 27.8‘ grains‘ of 4-'amino-4'-nitro-'
diphenyl sulfo-ne, '75 cc. of acetone and 14 grams
of‘ thiodiglycolic anhydride‘ was ‘re?uxed for two
tions Nos. 5 and 6.
N -diglycolyl -4,4’ —diaminodimhény1 sulfone
hours. At this'itime, 100 ‘ccjof "water was added
and the acetone wasv evaporated from the mix“
ture. The solid material was?ltered off, washed
60 with water and dried at 80° C. The product of
this reaction was Néthiodiglycolyl-4-amino-4’
nitrodiphenyl sulfone. A_ mixture of 41.0 grams
of this ‘product with 35.7 grams of granulated tin
in 250 cc. of alcohol was stirred with250 cc. of
A mixture of 24.6 grams of 4-amino-4'-nitro
diphenyl sul?de,»75 cc. of acetone and 12 grams of
diglycolic-anhydride was re?uxed for two hours
and thereafter allowed to stand for ten hours at
10% hydrochloric acid at 40°'—45° C. for 'four
hours. Solids were removed by ?ltration. and
the ?ltrate was freed from tin bytreatment with
hydrogen sul?de. Excess hydrogen sul?de was
dissipated by means of a‘st'ream of-air or by
25° C. The reaction product, N-diglycolyl-4 70 placing the solution undervacuum. >The solu
tion'wa's alkalinized with sodium bicarbonate,
amino-4’-nitrodiphenyl sul?de, was crystallized
evaporated to dryness under reduced pressure
from the mixture as a yellow solid and was ?l
and the residue was puri?ed by recrystallization.
tered off, washed with acetone and dried. The
QThe-Tnitro compound: also maybe-reduced with 1,
acetone :. mother: liquor, was evaporated. Water I
hydrogen? using a "hydrogenation“catalyst and“
was added to the residual oil and the'lmixturelwas
some suitable solvent, such as an alcohol, di~
The product was l'\vT--thiodiglycolyl-N'-ac'etyl-4,4'a
oxane, etc.
diaminodiphenyl sulfone.
As an alternative procedure, a molecular equiv
alent of N-acetyl-4A’-diaminodipheny1 sulfone,
N-dz‘thz'odiglycoZyZ-4,4'-diaminodiphenyl sulfone
prepared according to the method described in
J. Am. Chem. Soc, 61, 2763 (1939), or the method
described in United States Patent No. 2,260,626,
issued October 28, 1941 to Kleiderer and Van
Arendonk, may be reacted with a molecular equiv
alent of thiodiglycolic anhydride, using the meth
od of the present example, to produce the prod
This product may be prepared according to the
method of Example II, using monomethyl di
thiodiglycolyl chloride in place of thiodiglycolic
anhydride, with corresponding changes in the
stoichiometrical proportions. The monomethyl
uct, N - acetyl - N’-thiodiglycolyl-4,4’-diaminodi
phenyl sulfone, which is identical with the prod
uct described hereinbefore in the present example.
Other mixed N-acy1-4/l’-diaminodiphenyl sul
compounds embodying the acyl residues de
residue of the derivative as thus prepared may
rived from the anhydrides described herein may
be hydrolyzed off by conventional methods, for
also be prepared by the methods described in the
example, by re?uxing the material in acetone so
examples. Among these acyl de
lution with caustic soda. .
20 rivatives are the following:
N - thionyldiglycollyl- 4,4’ -diamz'nodiphenyl sulfone,
N - diglycolyl-N ' -acetyl
0: s 40O—1\II-(ILJ—CHZ—Q~CH:—C 0 0H
N-dithiodiglycolyl-N’ -acetyl
N-thionyldiglyc olyl-N’ -acetyl
N-sulfondiacetyl-N’ -acetyl
In place of the anhydrides described hereinbe
fore, the acyl halides or the mono-ester acyl hal
This product may be prepared according to the
ides of the acids may be employed. In this event,
method of Example II, using thionyldiglycolic 30 after condensation of the acyl dihalide or the
anhydride in place of thiodiglycolic anhydride,
mono-ester acyl halide with an amino group, the
with corresponding changes in the stoichiometri
hydrolysis of the residual halide or mono-ester
cal proportions.
residue is made necessary in order to'expose the
free carboxyl radical of the acid residue.
N H2
As a further alternative, the diaminodiphenyl
sulfone or 4-nitro-4'-aminodiphenyl sulfone may
be condensed With the acid directly, forming ?rst
an amine salt and subsequently dehydrating the
amine salt with the aid of heat and, if desired,
40 a dehydration catalyst to accelerate the reaction.
This compound may be prepared according to
the method of Example I, replacing diglycolic an
hydride with sulfondiacetic anhydride.
It is further a feature of this invention that
sulfondiacetic anhydride may be replaced with
thiodiglycolic anhydride and the sul?de radicals
of the thiodiglycolyl and aminodiphenyl sul?de
‘residues oxidized simultaneously with an excess .
The dehydration reaction may be conducted at re
duced pressure.
The derivatives of the present invention may be
recovered as the hydrates. For example, N,N’-di
thiodiglycolyl-4,4’~diaminodiphenyl sulfone may
be recovered as the dihydrate and N,N'-di-digly
colyl-llfl'-diaminodiphenyl sulfone as the trihy
drate. This water of hydration may be removed
by heating the respective compounds in a stream
of hydrogen peroxide to the corresponding sul
fones. For example, the diglycolic anhydride of
.of heated air or in vacuo below the temperature
Example I may be replaced with 14 grams of
1. A substituted 4,4’-diaminodiphenyl sulfone
which is represented by the formula:
thiodiglycolic anhydride and the quantity of 30%
hydrogen peroxide increased to 63.4 00., or twice ,
at which decomposition begins.
I claim:
that required for the oxidation of one sul?de'resi
due to the corresponding sulfone residue.
N - thiodigZycoZyZ-N’ -acetyZ-4,4' -dz'aminodiplhenyl .
A mixture of 41 grams of N-thiodig1ycolyl-4,4'
diaminodiphenyl sulfone, prepared according to
the method of Example II, '75 cc. of acetone and
11 grams of acetic anhydride was refluxed for two .
hours. 106 cc. of Water Was added and the ace- _
represents a residue selected from the group con
sisting of diglycolyl, thiodiglycolyl, dithiodigly
colyl, thionyldiglycolyl and sulfondiacetyl res—
2. The product set forth in claim 1 in which the
carboxyl hydrogen is replaced by a metal ion
selected from the group consisting of alkali-metal,
tone was evaporated. The solid material was ?l
alkaline-earth metal, ammonium and substituted
tered off, Washed with water and dried at 80“. C. - 75 ammonium ions.
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