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2,407,309
Patented Sept. 10, 1946
UNITED STATES PATENT OFFICE
‘ CHEMOTHERAPEUTIC AGENTS OF THE
SULPHONAMJDE TYPE
William A. Lott, Maplewood, Frank H. Bergeim,
Highland Park, and Kathryn A. Losee, New
Brunswick, N. J., assignors to E. R. Squibb &
Sons, New York, N. Y., a corporation of New
York
No Drawing. Application February 4, 1942,
Serial No. 429,578
5 Claims. (01. 260'—397.7)
1
2
are obtained, which may be converted into the
This invention relates to, and has for its object
the provision of: (A) (Amino-benzene-sulphon
amido) -aminophenol ethers; (B) salt-type
derivatives thereof; (C) intermediates formed in
corresponding amino compounds by hydrolysis.
'
The (amino-benzene-sulphonamido) - amino
phenol ethers are generally amphoteric com
pounds, forming acid-addition salts with hydro
the preparation of (A) ; and (D) methods of pre
paring (A), (B) and (C). Compounds (A) and
(B) are valuable chemotherapeutic agents, being
especially promising as antimalarials.
The invention comprises especially: (A) com
10
pounds of the general formula
chloric, sulphuric, boric, nitric, lactici, tartaric,
and other acids commonly used to solubilize
amine bases, as well as salts with bases, for ex
ample the alkali-metal bases and organic-amine
bases. Some of the salts, it should be noted, are
insoluble or only slightly soluble in water.
Compounds (B) also comprise salt-type deriv
atives in which R and/or R4 represent sali?ed
groups such as the following:
15
(I)-CO—(CI-Iz)n—COO-—(alkali metal( where
in n is an integer from 2 to 5
wherein R, R',‘ R2, R4, and R5 represent each a
member of the group consisting of hydrogen, hy
drocarbon (preferably lower alkyl), substituted
(11)
hydrocarbon (preferably dialkylaminoalkyl) , and 20
acyl (including sulphonyl) radicals, and R3 repre
(lower alkyl)
—-CH
SOs--(alkali metal)
(III) -'-alkylene—SO2—-(alkali metal)
sents a member of the group consisting of hydro
Thus, compounds embodying group (I) may be
obtained by reacting the (amino-benzene-sul
phonamido) -aminophenol ether with the ap
icals; (B) salt-type derivatives of (A); (C) in 25 propriate
aliphatic dicarboxylic acid anhydride
termediates formed in the preparation of (A);
(especially
succinic anhydride), and converting
and (D) methods of preparing (A), (B) and (C).
the resulting acid (e, g., succinamic acid) into the
The method of preparing the compounds of this
corresponding alkali - metal - including am
invenion essentially comprises condensing a com
monium-salt;
compounds embodying group (II)
30
pound of the group consisting of nitro-amino
may be obtained by adding the (amino-benzene
phenol ethers, alkylamino-amino-phenol ethers,
sulphonamido)~aminophenol ether to a solution
and acylamino-amino-phenol ethers with a mem
of sodium bisulphite and a lower aliphatic alde
ber of the group consisting of nitro-benzene-sul
hyde,
heating the mixture until a clear solution
phonyl halides, alkylamino-benzene-sulphonyl
halides, and acylamino-benzene sulphonyl hal 35 is obtained, isolating the crude product by evapo
rating the solution to dryness, and purifying the
ides. When the compounds are prepared from
crude product, e. g., by recrystallization from
the nitro-amino-phenol ethers and/or the nitro
diluted 95% alcohol; and compounds embodying
benzene-sulphonyl halide reactants, there are
group (III) may be obtained by reacting the
produced intermediate nitro compounds of the
(amino-benzene - sulphonamido) - aminophenol
40
general formula
ether with an alkali-metal aldehyde-sulphoxylate
carbon (preferably lower alkyl) and substituted
hydrocarbon (preferably dialkylaminoalkyl) rad
(e. g., sodium formaldehyde sulfoxylate) in a suit
able solvent (e. g., glacial acetic acid). If the
(amino-benzene - sulphonamido) - aminophenol
R2
X
wherein R2 and B3 have the above-given meaning,
and one of the X’s represents a nitro radical and
the other represents a member of the group con
sisting of nitro, alkylamino, and acylamino rad
icals; and these nitro intermediates are converted
to the corresponding amino compounds by reduc- 7
tion or catalytic-hydrogenation. When the com
pounds are prepared from the acylamino-amino
45 ether has both amino groups available, compounds
in which both R and R.4 represent such sali?ed
groups are obtained. To obtain a compound in
which R. alone ‘represents such a group, an
(amino-benzene -_ sulphonamido) - nitrophenol
ether is used as the reactant, and the resulting
nitro salt-type derivative is then catalytically-hy
drogenated to the corresponding amino salt-type
derivative; and to obtain a compound in which R4
alone represents such a group, a (nitro-benzene-r
phenol ether and/or acylamino-benzene-sul
phonyl halide reactants, acylamino compounds 55 sulphonamido) -aminophenol ether is used as the
2,407,309
3
4
reactant, and the resulting nitro salt-type deriv
phonamido)~5-amino-anisole melts at 186-8o C.
ative is then catalytically-hydrogenated to the
(uncorrected) .
corresponding amino salt-type derivative.
The following examples are illustrative of ‘the
invention:
5
EXAMPLE 1
SULPHONAMIDO) ~5-NITR0-ANIS0LE
acetamino-benzene-sulphonyl chloride are ground
together in a mortar, and 40 cc. pyridine is added,
forming a dark-brown solution which soon be
comes very viscous. The solution is heated for an
hour on a steam bath, and several volumes of cold
Water is then added thereto with stirring. The
gummy precipitate formed, which later becomes
granular, is ?ltered off and washed with water.
adding ether (or by evaporating the alcoholic
solution to dryness).
quantity of a dilute aqueous solution of hydro~
chloric acid.
(2) PREPARATION or THE SODIUM SALT or 2-(P
The product, crude 2-(p-acetamino-benzene-sul
C. (Fisher melting-point block), may be used
without further puri?cation,
and a moderate excess
(over the equivalent
quantity) of alcoholic sodium hydroxide is added.
The solution is then evaporated to dryness in
vacuo to give the sodium salt of Z-(p-amino
2 - (p-acetamino-benzene-sul
benzene - sulphonamido)-5-amino-anisole.
An
aqueous solution of the sodium salt may be pre
pared Without isolating the salt by adding the 12
(p - amino - benzene-sulphonamido) -5-amino
and cooling, a crystalline precipitate ‘forms, and
anisole to the requisite quantity of a dilute aque
ous solution of sodium hydroxide.
is ?ltered oif and washed several times with alco
product,
ANISOLE
amino-anisole is suspended in boiling alcohol,
phonamido) -5-nitroanisole is added to a mix
ture of 500 cc. alcohol and 500 cc. 10% hydro
chloric acid, and the mixture is re?uxed until
a clear solution is formed and for one hour there
after. On removal of the alcohol (by distillation)
The
AMINO - BENZENE - SULPHONAMIDO - 5 - AMINO
The 2 - (p-amino-benzene-sulphonamido.) -5
(b) PREPARATION or Z-(P-AMINO-BENZENE
SULPHONAMIDO-5-NI‘1‘R0-ANISOLE
hol.
An aqueous solution of the
hydrochloride may be prepared without isolating
the salt by adding the 2-(p-amino-benzene-sul
phonamido)~5-amino-anisole to the requisite
phonamido) -5-nitro-anisole, melting at 202-208° 20
crude
HYDROCHLO
amino-anisole is dissolved in absolute alcohol,
an equivalent quantity of diy hydrochloric acid
is added thereto, and the salt is precipitated by
56 g. 5 - nitro-Z-amino - anisole and 78 g. p
g.
PHONAMIDO) - 5 - AMINO - ANIsoLE
RIDE
The 2 - (p—amino-benzene-sulphonamido) -5
(a) PREPARATION or 2-(P-ACETAMINO-BENZENE
50
(d) PREPARATION or Z-(P-AMINO-BENZENE-SUL
2 - (p-am-ino-b‘enzene~sul
(f) PREPARATION on THE DI- (SODIUM FoRMALnE
HYDE SULPHOXYLATE) DERIVATIVE or 2-(P
phonarnido) -5-nitro-anisole, melts at 173-4" C.
(c) PREPARATION or Z-(P-AMINO-BENZENE
AMINO - BENZENE - SULPHONAMIDO) - 5 - AMINO
ANIsoLE
SULPHONAMIDO).-5—AMINO-ANISOLE
A mixture of 8.8 g. z-(p-amino-benzene-sul
Procedure I
20 g. 2-(p-amino-benzene~-sulphonamido)-5 40 phonamido)-5-amino-anisole and 11 g. sodium
formaldehyde sulphoxylate is added with stir
nitro-anisole is suspended in 225 cc. aqueous
ring
to 15 cc. glacial acetic acid. When a clear
acetic acid, and treated with hydrogen under
solution is obtained, ether is added until a solid
atmospheric pressure in the presence of Adams’
precipitate forms. The precipitate is ?ltered off,
platinum catalyst, until approximately 4,630 cc.
hydrogen has been absorbed. The catalyst is
removed from the reaction mixture by ?ltration;
and the ?ltrate is concentrated under reduced
pressure to give a solid, which is dissolved in
dilute aqueous hydrochloric acid. The solution
is treated with decolorizing carbon and ?ltered,
and the free base is precipitated by adding di
lute sodium hydroxide; and the product is fur
ther puri?ed by dissolving it in excess dilute so
washed with ether, and dissolved in a small
amount of water, and the solution is neutralized
with sodium bicarbonate on addition of alcohol
and cooling, the inorganic salts precipitate out
and are removed by ?ltration.
Ether is then
added to the ?ltrate, and the crystalline precipi
tate formed is ?ltered off, washed, dried, and
puri?ed by recrystallizing from 50% alcohol.
The product is a derivative of 2-(p-amino-ben
dium hydroxide, ?ltering, and adding dilute
zene - sulphonarnido) -5-amino-anisole in which
hydrochloric acid until no further precipitation
groups.
occurs.
both R and R4 are methane sodium sulphinate
On recrystallization ‘from aqueous alco
hol, the product, .Z-(p-amino-benzene- sulphon
amido)-5-amino-anisole, melts at 181-2" C.
(a) PREPARATION or THE MONO-(SODIUM FORM
ALDEHYDE SULPHOXYLATE) DERIVATIVE OF 2-(P
AMINO - BENZENE - SULPHONAMIDO) - 5 - AMINO
Procedure II
20 g.‘ 2-(‘p-amino-benzene~sulphonamido)-5
nitro-anisole and 20 g. powdered iron are mixed
in a mortar; and 80 cc. acetic acid is then heated
to about ‘70° vC., and the mixture is added there
to in small portions so that a mild ebullition
60
ANISOLE
A mixture of 9.7 g. 2-(p-amino-benzene-sul
phonamido) -5-nitro-anisole and 5.5 g. of sodium
formaldehyde sulphoxylate is added with stirring
to 15 cc. glacial acetic acid. When a clear solu
tion is obtained, ether is added until a solid pre
continues throughout the reaction. Suf?cient
cipitate forms. The precipitate is ?ltered off,
water is added to hydrolyze the acetate and pre
washed with ether, and dissolved in a small
cipitate the amine base, and the liquid is re
amount of water, and the ‘solution is neutralized
moved from the solid by centrifugation. The
with sodium bicarbonate; on addition of alcohol
solid, containing the product and excess iron, is 70 and cooling, the inorganic salts precipitate out
extracted twice \with 10% sodium hydroxide;
and are removed by ?ltration. Ether is then
and the centrifuged supernatant is ?ltered and
added to the ?ltrate, and the crystalline precipi
made just alkaline to Congored. The precipi
tate formed is ?ltered off, washed, dried, and
tate is ?ltered, and recrystallized from 50% alco
puri?ed by recrystallizing from 50% alcohol,
hol; the thus-obtained Z-(p-amino-benzene-sul
This nitro compound is then dissolved in alcohol
2,407,809.“;
6
2 -(p-amino-benzene4sulphonamido) - 4 - amino
and hydrogenated, using Adams’ platinum‘ oxide
catalyst. The product is a derivative of 2-(p
anisole in which both R and R4 are‘ u-ethane
amino - benzene-sul'phonamido)-5-amino-aniso1e
sodium sulfonate groups.
in which R is a methane sodium sulphinate
(e) PREPARATION or 'I'HE Morro-(Acnrarnsnvnn
SODIUM BISULPHITE) DERIVATIVE or 2- (P-AMINO
group.
'
'
'
-
56 g. e-nitro-z-amino-anisole and 78 g. p
_
.BENZENE-SULPHONAMIDO) -4—AMINO-ANISOLE
EXAMPLE2
(a) PREPARATION OF 2- (P-AClilTAMINO-BENZENE~
SULPHONAMIDO) -4—NITRO-ANISOLE
.
‘ To a saturated solution of 16.9 g. sodium bisul
phite in 25 cc. water is added 7.1 g. acetaldehyde,
10 .and the mixture is stirred for about one hour.
Then 50 g. of well-ground :Z-(p-amino-benzene
sulphonamido)-4-nitro-anisole are added to this
acetamino - benzene - sulphonyl chloride are
ground together in a. mortar, and'40 cc. pyridine
is-added; and the dark-brown solution formed,
which soon becomes very viscous, is heated on a’
solution, and the mixture is heated on the steam
bath for about one hour. The clear solution is
phonamido)-4-nitro-anisole, melting at 254-8°
20 amino-benzene-sulphonamido) - 4-,amino-anisole
steam bath for an hour, and several volumes of 15 then concentrated to dryness, and the product
puri?ed by recrystallization from 95% alcohol.
cold water is added with stirring. The gummy
This nitro compound is then dissolved in alcohol,
precipitate formed, which later becomes granular,
and hydrogenated, using Adams’ platinum oxide
is' ?ltered off and washed with hot water; the
catalyst. The product is a derivative of 2-(p-v
product, crude 2 - (p-acetamino-benzene-sul
C. (Fisher melting-point block), may be used.
in which R is an a-ethane sodium sulphonate
without further puri?cation.
group.
~
The 2 -(p - amino~benzene-sulphonamido)~4
V
amino-anisole may be converted into various other
SULPHONAMIDO) -4-NITR0 -ANISOLE
salt-type derivatives thereof, by theprocedures
detailed in (d), (e), (f), and (g) of Example 1.‘ . _
'70 g. of the crude 2-(p-acetamino-benzene
sulphonamido) -4-nitro-anisole is added to a
EXAMPLE 3
mixture of 700 cc. alcohol and ‘700 cc. 10% hydro~
(a)
PREPARATION
OF
3-NITRO - 4 -' (P-ACETAMINO-l
chloric acid, and the mixture is re?uxed until a
BENZENE-SULPHONAMIDO)
-ANISOLE
clear solution is formed and for one hour there 30
after. On removal of the alcohol (by distillation)
Procedure I
and cooling, the hydrochloride of 2-(p-amino
168 g. 3-nitro-4-amino-anisole is intimately
(b) PREPARATION or Z-(P-AMINO-BENZENE-
benzene-sulfonamido) -<l-nitro-anisole separates,
mixed with 233.5 g.v p-acetamino-benzene-sul
and is ?ltered off. The freev base, obtained by
.phonyl
and the mixture is treated with
suspending the hydrochloride in water and add 35 120 cc. chloride,
pyridine. - On additionof water to the
ing an‘ equivalent quantity of dilute sodium hy
resulting dark solution, 3-nitro-4-(p-acetamino
droxide solution, melts at 188-190° C.
benzene-sulphonamido) -anisole is precipitated
as a granular material. The product is ‘puri?ed
(c) PREPARATION or‘ 2-(P-AMINo-BENzENE-; by dissolving it in dilute aqueous alkali, reprecipi
SULPHONAMIDO) -4—AMINO-ANISOLE~
40 tating it by acidifying the‘ solution, and recrystal
.10 g. 2-(p-amino-benzene-sulphonamido) -4
lizing from 50% alcohol, and then melts at
nitro-anisole and 10 g. powdered iron are thor
oughly mixed in a mortar; 40 cc. acetic acid is
173-4” C. (uncorrected).
Y
Procedure II
168 g. B-nitro-‘l-amino-anisole is dissolved in,
336 cc. pyridine, using alittle heat if necessary.
then heated to about 70° C., and while agitating
the acetic acid in a flask, the mixture is added
thereto in small portions at such rate that a mild
ebullition continues throughout the reaction.
Solid p-acetamino-benzene-sul-phonyl chloride is
then stirred into this solution gradually, not allow
The reaction mixture is then cooled, sufficient
ing the temperature to rise above 50° C.‘ After
water is added to hydrolyze the acetate and pre
cipitate the amine base, and the liquid is removed 50 standing a few hours at room temperature, the
from the solid portion by centrifugation. 300 cc.
solution is diluted with water, and made acid to 7
Congo red with hydrochloric acid. The product
10% sodium-hydroxide solution is added to the
precipitates as a yellow-orange crystalline prod- Y
uct, and on recrystallizing from alcohol, melts at .
solid, and the mixture stirred thoroughly and ,_
centrifuged; and the solid is again extracted with
10% sodium hydroxide solution and centrifuged.
On ?ltering the supernatant and making it just
alkaline to Congo red, the product, Z-(p-amino
173-4° C.
(b) PREPARATION or 3-NITRO-4-(P-AMINO-BEN
‘
benzene-sulphonamido) -4-amino anisole, precipi
'
ZENE-SULPHONAMIDO) -.ANISOLE
175 g. 3-nitro-4-(p-acetamino-benzene-sul
tates as a light tan powder. After recrystalliza
tion from 50% alcohol, it melts at 231-3° C. 60 phonamido) -anisole is digested for an hour with
3500 cc. of a 1:1 mixture of 10% aqueous hydro
(uncorrected).
chloric acid and alcohol, the compound gradually
(d) PREPARATION or THE DI-(ACETALDEHYDE-SO
going into solution; and the solution is then
rnnvr BISULPHITE) DERIVATIVE or 2-(P-AMINQ
._ BENZENE-SULPHONAMIDO) -4-AMmo-AmsoI.r:
cooled, and adjusted to a pH of about 5-6 by the
65 addition of 40% sodium hydroxide solution. The
thus-precipitated yellow granular substance,
' To a saturated solution of 3.5 g. sodium bisul
3-nitro - 4 -(p - amino - benzene-sulphonamido) -
phite 1116 cc. cold water is added 1.8 cc. acetalde-‘
anisole, after puri?cation by recrystallization
hyde',‘ and'the mixture is stirred for-about one
hour.‘ Then 5 g. 2e(p-amino-benzene-sulphon
amido) -4-amino-anisole is added to this solution,
from alcohol, melts at 118-9° C.
(c) PREPARATION OF 3-AMINO-4-(P-AMINO-BEN-L
ZENE-SULPHONAMIDO) —ANISOLE
Procedure I
and the mixture is heated on the steam bath for
about one hour, at the end of which time there is
a"'cle’ar solution. The solution is evaporated to
dryness, and the product is recrystallized from
95%‘ alcohol.‘ The product is a derivative of
75 t
30 g. 3-,nitro-4-(p-amino-benzene-sulphonamie ,
do) ‘-anisole is added gradually to a hot suspension ‘
2307:3092?
851
oiasa-zgsziron powder-rm; axsolution: of- 31 ‘cc: con
centrated hydrochloric acidr'inz276xcc; 952%.» 8.100.;
hol. After addition of all5ofathe; nitrorcompound;
o?‘;l andrthez?ltrate; concentrated rJinavacuum .at;
40? G3‘; after: crystallization from; absolute alcohoh.
the:product; 3samino+4eacetaminosanisole; melts;
the mixturelis re?uxed. for- about .15 hours, ,while .
stirring, andltl'ieironpowder. i‘s?thens?lteredm?' 5
13 g. p-acetamino-benzene-sulphony1 chloride;
and "thoroughly, ext‘ract'erLWith" hot- 95%.Ia1col'1ol.
is added slowly, witlir.coolirig;'_tb 13 cc. pyridine,
The ?ltrate and‘al'coholic extract are combined,
andthesolutionis,.added slowly, with cooling to.
acidi?ed to Congo red with alcoholic- hydrochloric
a suspensionlof; 10' g....3laniinoAeacetamino-ani;
acid; and ‘evaporated ‘to -dryness‘underfsubatmo's=
sole in 15"cc. pyridine. The deep red liquid
pheric pressure. The residue’, crude 3-amino; 10.1‘ formed is allowed ‘ to ‘ stand iorvan hour; and cold
4'-(peamino-benzeneesulphonamido)'-anisole hy--~
waterl‘is'aadd'ed thereto; and theIred‘granular-pre'
drochloride; is dissolved'ini water; andl'the‘solu-i
cipitat‘ezformedis ?ltered‘off, washedv with water;
tioniisl treated with decol'oriz‘i‘ng carbon» and-‘?l
and Precrysta'llized from"5'0i%i alcohol.‘ The ¢pr0d-tered“; ‘andtheiree-base- is precipitated ‘from the“
uct; 3'-(p~acetaminoebenzeneesulphonamido>¢4h
?ltrate-by adding dilute .sodiumshydroxide; The’ 150 acet'amihmani‘sole; melts‘ at” 230-1“ C; (uncorev
precipitate; a pi-nkish-crystallinev material; isrrer
rected);
crystallized from'nebutanollto- give the‘ B’Lamino-W
(by) PREPARATION- on 3.-(AMINO.-BENZENE-:SUL.=
4- (p-amino-benzeneesulphonamido) r-ranisole as;v
anialinost pure, white crystalline-anaterial melt:
PHONAMIDO.) ~4rAMINO-ANISOLE.
201g: 3- (paacetamino-benzene-sulphonamido)’--
20*
d'hacetamino-anisole; 200- cc; 10%‘~ hydrochloric‘
acid, and 20 cc. alcohol (to prevent foamingY-are
boiledfor an hour; and the clearsolutioniormed
10‘, g. 3-'nitro=4;-(p>amino=benzene'-sulphona
is ?ltered; cooled; and made just allialineto Congo
midor-anisole and 10. g: powdered‘iron' are‘ mixed '
in any mortar; 20 cc: acetic acid isthen‘heate'd‘to'; 25-? red by the addition of 10% sodium hydroxide,
a lightecoloredvx precipitate being formed. The
70° 0., and " the“ mixture‘ added‘ thereto in" small
precipitate,’ 34 (p-amino-benzene-sulph'onamido) ‘- '
amounts just fast enough .t'ocause mild ebullition
4-amino—anisole,- is‘ ?lteredi off, and after re-r
throughout the reaction. Su?lcient water isthen.
crystallizationfrom 50%‘ alcohol,-melts at?178-9°"
added‘ to. the... cooled. reaction. mixture, to hy
drolyze the acetate and precipitate the amine 30-‘ C. (uncorrected) ';
base, and the liquid islremoved by centrifuging.
EXAMPLE ,5.
Thelsolid portion is-ex-tracted twice with 10%
(a) '‘ PREPARATION‘ OF " 3’-I(P=NITRor-BENzENEeSUL'-~
sodium‘ hydroxide, centrifuged and-.the superna
PHONAMIDO) -4'-AcETAMINo'-AmsoLE;i
tant .liquid. ?ltered; and.v the: ?ltrate isvmade- just .
acid to: Congo r.ed..v The-precipitate, 3.-amino-4.~
15.2, g, vp-nitrorhenzenersulphonyl. chloride is
(p;aminosbenzene=sulphonamido)._-anisole,. after
slowly addedtov, 15 cc. pyridine, While'cooli'ng,
recrystallization from 50%;» alcohol, melts, atv
and the solution is slowly added‘to a suspension
194+5-9 C. (uncorrected);
of 15; g;.; 3ramino-4aacetamino-anisole;in’. 20 cc.
pyridine; while ;c0®1ing_:,. The" deep-orange reac
Procedure II
Procedure. III .
tion mixture is allowed to stand for an hour, and
5 g; 3-nitro-4-(p-acetamino-benzene-sulphonw
cold water'is added thereto, a'granular orange
ture isadded theretoin small portions just fast.
enough tocause a mild‘ebullition throughoutthe:
reaction. The?mixture is cooled,‘ ,an‘dtsu?lcient"
andafter recrystallization-from alcohol,‘ it‘ melts
at 183-5°1C. (uncorrected).v
precipitate being formed. The~precipitatey 34>
mido)-anisole (cf. Example-31m) and-5 g; pow;
(p-nitro-benzene-sulphonamido) - 4 -l acetamino»
dered iron are mixe'dlina" mortar; 10 cc. acetic
acidis then heated to about 70° C., andthe mix- 45 anisole, is ?ltered o?- and washed'with water;
water isadded tov hydrolyze‘ the acetate and ‘.
precipitate the amine base, and the liquid‘ is‘re- 50
moved'by centrifuging. The. soli'dportion' is;ex-‘
tracted twice with 10%, sodium hydroxide; and‘.
the extract is centrifuged‘ and; the supernatantv
(b) ; PREPARATION‘ on 33-(P-AMINQ-BENZENE-,-SUL.
PHONA'MIDO)é‘l-ACETAMINOe-ANISOLE
12.5 g. 3-'(p-nitrorbenzenersulphonamido),-4+i
acetamino-anisole. in. 250' cc.. alcohol. is hydrogenated in the .presence of Adams? platinum oxide
catalyst. The. catalyst is. ?ltered off . and the .?l-L
?ltered‘ and" made just alkaline to Congo red.‘
The product, 3lamino-ll-(p-acetamino-benzene= 5;, trate concentrated. in. vacuo; the residue,‘ 3-6p
sulphonamido)-anisole, after recrystallization
amino» benzene. -- sulphonamido) - 4- acetamino
anis0le,. after recrystallization. from. alcohol,.
fromialcohol, melts>-.a-t11"7l“-3°"C. (uncorrected) ..
The 3—amino-4=>(p> acetaminoi-benzene - sul
meltsuat. 155-7?’ C. .(uncorrected)...
phonamido).-anisole.. is. then converted into..- 3
amino=4-. (p-aminosbenzenersulphonamidmranir 6O
sole. by.hydrolysis with.1.0 %, aqueous :hydro chloric.
PREPARATION OF 2-AMINO-4-(P—AMINO=BENZENE*
acidas detailed inExampleB .(b)...
SULPHoNAM1no).-ANIsoLE.
The 3'-amino.-4-.(praminorbenzene-sulphonae
mido).-anisole, may. be. converted’, into. various.
2"'-acetamino-4i-n»itro=anisole'- is} hydrogenated
saltet'ype derivativesby the, proceduresldetailedl. 65 in alcohol" in the» presence»- of" A’dams’~~ platinum
in (6), (hand (9) ofv Example 1; andinidl and.
oxide. catalyst. Thev catalyst is ?ltered o?, and
(e). of..Examp.le.2..
the ?ltrate concentratedin vacuo.v The product,.
.
2-acetamino+4éamin0eanis0le,. after recrystallii
4.1
(a); PRneARAnom or" as (P-ACETAMINO'P‘BENZENE'T
SULPHONAMIDO'XL- 4LACETAMINO1-ANISOLE
30 g. 3-nitro-4-acetamino+anisole is suspended
in 600 cc. alcohol and hydrogenated, using Adams’
zation. from ,alcohol, melts. at. 107-8“ ‘ C. (uncor;
7
0
rected)§.,
The.
2-acetamino-4-aminoranisole., is
densed’ with
con:
p-acetarninmbenzene- sulphonyl’
chloride-e. g. in themanner. describedin Exam
ple 4‘ (ab-and the, resulting 2»-acetamin0,-4=:-v
platinum oxide. catalystl Thegcatalystis?ltered. 75, (p
- acetamino - benzene- sulphonamido)‘ - am:
2,407,309
10
dure- III) is mixed with 16g. pyridine, andthen
gradually treated with 13 g. ethyl-sulphonyl
fsole" (M. P. 242-4° 0.)‘ is“v hydrolyzed—e. g. in the
manner described in Example 4(b)—-to obtain
After standing for an hour, the mix- _
‘2 - amino - 4 - (p - amino - benzene - sulphona -
- chloride.
mido) -anisole (M. P. 172—3° C.).
ture is diluted with 300 cc. ice water, and the
gummy precipitate which ?rst forms and soon
becomes granular is ?ltered off and Washed with
water. The product,. S-(ethyl-sulphonamido) -
‘
EXAMPLE 7
PREPARATION OF 2-AcE'rA1vrINo-4-(P-AMINO-BEN
ZENE-SULPHONAMIDO) -,ANISOLE
4(p-acetamino-benzene-sulphonamido) - anisole,
is then ‘digested for one hour with 300 cc. 10%
"2-acetamino-4-amino-anisole is condensed
hydrochloric acid, whereupon it gradu
with p-nitro-benzene-sulphony1 chloride-e. g. 10 aqueous
ally’enters
solution therein.’ After cooling and
‘in the manner described in Example 5(a), and
?ltering off a small amount of undissolved mate
‘the resulting 2-acetamino-4-(p-nitro-benzene
rial, the solution is neutralized to about pH 6 by
sulphonamido)-anisole (M. P. 214-5" C.)_ is re
the addition'of 10% aqueous sodium hydroxide.
'duoed-—e. g.'in the manner described in Exam
ple 5(b)-—-to obtain 2-acetamino-4-(p-amino 1:5 The resulting granular precipitate, 3-(ethy1-su1
phonamido) -4-(p - amino - benzene - sulphona benzene-sulphonamido) -anisole.
mido)-'anisole, isobtainedas ‘a white crystalline
material by recrystallization from 50% alcohol.
EXAMPLE 8
(a) PREPARATION or 3-NITRO - 4 - (P-ACETAMINO
I ‘BENZENE-SULPHONAMIDO) -PHENETOLE
PREPARATION OF 3-(P-AMINo-BENzENE-SuLPHoN
100 g. 3-nitro-4-amino-phenetole and 128.4 g.
.p-acetamino - benzene - sulphonyl
chloride
v EXAMPLE 10
20
AMIDO) -4-DIMETHYLAMINO-ANISOLE
are
'
mixed in a mortar, and 66 cc. pyridine is added
3-nitro-4+dimethylamino-anisole is hydrogen
thereto“ A dark-red liquid is formed, with evo 25 'ated in alcohol in the presence of Adams’ plati
lution of heat, The reaction mixture is heated
num woxide catalyst to Obtain 3-amino-4-di
onthesteam bath for a half hour, and cold wa
methylamino-anisole.
ter is added thereto; and the granular orange
18 g,
‘formed, 3-nitro-4-(p-acetaminO-ben
. product
v
'
3-amino-4 - dimethylam'ino- anisole ' is
mixed with 24 g. p-acetamino-benzene-sulphonyl
zene-sulphonamido) -phenetole, is ?ltered OE and 30. chloride, and then treated with 12 g. pyridine. A
washed with water. On recrystallization from al
thick solution forms,.which soon becomes warm
coholgitgmelts at 154-5“, C. (uncorrected) .1
and viscous. .After an hour, this solution is
treated with 250 cc. water; and the gummy pre
.(b) PREPARATION or 3-NrrRo - 4 - (P-AMINO-BEN
cipitate of 3-(p-acetamino-benzene-sulphona
ZENE-SULPHONAMIDO) -PHENETOLE
-- ' 293
g.
mido) -4-dimethylamino-anisole formed is rubbed
After thor
oughly washing with water, 25 g. of the acety
lated compound ishydrolyzed by digesting with
_ up‘ with water until it granulates.
3' - nitro-4-(p-acetamino-benzene-sul
-phonamido)-phenetole, 2.930 liters 10% hydro
chloric acid, and 25 cc. alcohol (to prevent foam
ing) are boiled together for 1% hours. The clear
solution formed is ?ltered, and then cooled.
Some of the product precipitates out (as the hy
drochloride) on cooling, and is converted to the
free base by suspending in water and adding so
250 cc. 10% hydrochloric acid for an hour. After
cooling and ?ltering off any undissolved materi
al, the solution is neutralized to a pH of'about 6
by‘m'eans of‘ adueous sodium hydroxide solution;
the
dium'hydroxide until just alkaline to Congo red.
The ?ltrate (obtained on removal of the hydro
product, ' 3-(p-amino - benzene - sulphona
"mido)—47dimethylaminoeanisole separates as .a >
45
chloride) also is made just alkaline to Congo red,
precipitating the 3-nitro-4-(p-amino-benzene-'
granular solid, and is obtained practically ‘white
and crystalline by recrystallization from 50% al
I cohol.
sulphonamidm-phenetole as an orange powder,
which is then recrystallized from alcohol (M. P.
114-6n
C.).
‘
r
11 ’
50 (d) it PREPARATION OF .3-NI1'Ro-N-(P-TOLYLSUL
'
'(c) PREPARATION OF ‘3-AMINo-4-(P¢AMINo-BEN
‘
ZENE-SULPHONAMIDO) -PHENETOLE
'
10 g. 3-nitro-4-(p-amino-benzeneesulphona
mido) -phenetole and '10 g. powdered ironare
mixed in a mortar; then. 40 cc. acetic acid is
heated to about 70° C., ‘and the mixture added
thereto in small portions just fast enough to
.cause'mild ebullition throughout the reaction.
Su?icient Water is then added tohydrolyze the 60
acetate and precipitate the'amine base, and the
' liquid portion centrifuged Off.
The solid portion
is extracted twice with 10% sodium hydroxide
solution, and the supernatant obtainedby cen
trifuging is ?ltered ‘and “made I just alkaline 'tO
Congo red.
The precipitate, 3-amino-4-(p
vaminoebenzene-sulphonamido)‘-phenetole, is re
crystallized from 50% alcohol (M. P. 241-2° 0.).
EXAMPLE 9
PREPARATION ‘ or 3.- (ErnYL-SuLrHoNANIIno) -4- (P
'
AMINO-BE'NzENEj-SULPHoNAr/uno) -ANIsoLE
77533.5 g. of 3-amiriO-‘4(p-acetamino-benzeneesul
phonamido)-anisole (of: Example 3'(e)' Proce
PHONYL) - N - (,6 - DIETHYLAMINO - ETHYL) -} 4
' AMrNo-ANIsOLE
'30 g. 3-nitro-4-(p-tolylesulphonanflido) -anisole
is dissolved in 113 cc. absolute alcoho1 by heating
to boiling, and 15.5 g. ?-diethylamino-ethyl chlo
ride hydrochloride is ‘added’ thereto, followed by
27 .5 g. anhydrous potassium carbonate. The mix
ture is then‘ refluxed for several hours and ?ltered
hot; and the‘ ?ltrate is concentrated to a syrup
.under reduced pressure. The syrup is taken up
‘in benzene, 'washed several times with dilute so
dium hydroin'de, then with water, and dried; and
on distilling off the benzene, the 3-nitro-N-(p
tolyl-sulphonyl) -N- (,B-diethylamino - ethyl) -4
amino-anisole is left as an amber syrup.
(b) PREPARATION or 3-NI'rRo-4- (B-4DIETHYLAMINO
‘
,ETHYLAMINO) -ANISOLE -
_
10 g. 3 - nitro-N-2 (pétolyl-sulphonyl) -N- (pi-di
ethylamino-ethyl) -4-amino-anisole is mixed with
“25 cc. 90% sulphuric acid, andthe resultant solu
> tion is allowed to stand about 24 hours at room
temperature." The solution is then mixed with .
chopped ice, and strongly alkalinized'; and the
<11
12
.rliberated .base is v:taken up .in :benzene, ‘and the
solution .isidried and. distilled under; reduced" pres
sure. The product, '3enitroe4-(pediethylamino
sethylamino) ~aniso1e,':is obtained asia'red oil boil
::acetamino-benzeneqsulphonyl ‘chloride. .iAfterca
.rclear, dark-coloredssolution is:formed, it.'is.:a1
"lowed'to stand ~1several hours,.and1then diluted
with water. The iproduct, 3-.(p-acetamino-ben
zene-sulphonamido) -4-.carbamido - anisole, sepa
ito 'crystalsmeltingrat about :36-9° C‘.
rates as a gummy precipitate. It is dissolved in
.Thisfbase mayberconverted.tozits mono-hydro
chloride by dissolving:in ether ‘and'treating with
dilute ‘aqueous a-lkali,’treated with decolorizing
carbon, and reprecipitated by adding an excess
the requisite vvquantitypffan ethereal ‘solution ‘of
‘hydrogen chloride. On=puri?cation ‘by dissolving 1
of .dilutehydrochloric acid.
iinz-alcohol and "precipitating .with 5 ether, .‘it 1melts
The now granular
precipitate, the acetyl derivative, is .?lteredoff
:and washed. .Itis then .hydrolyzed.by-.digesting
'
forabout. an: hour withaqueous hydrochloric acid
('c) "PREPARATION "QWB-AMINO-ll-(pIDIETHYL
.andenough alcohol .to prevent .frothing. .The
productis .then .isolatedas aigranular solidby
-at.11~59+160° 'C.
.AMINO-JETHYLAMINO) -Ams0LE
neutralizing .to aboutpH 6 .with. aqueous sodium
.5. ;-.-g. .-.-3-nitro-él-. c?-diethylamino-ethyl). anisole
.hydrochlorideiis .dissolveddn<~200 cc. of;95‘% .al
cohol, . and, .hydrogenated gunder slightly greater
than atmospheric pressure using Adams’ platinum
oxide catalyst. Whenthreeequivalents of hydro :20
gen have been taken up, the catalyst is ?ltered off,
an‘d'the ?ltrate ‘evaporated to remove‘t'he "aqueous
alcohol. 'The-residue‘is‘?ltereddff, and the ?ltrate
evaporated .to :remove the aqueous alcohol, .and
...converted.to the .di-hydrochloride-of..3-,amino_4 "25
.(cediethylaminoeethyl) .-aniso1e.by adding ethe
real hydrochloric acid.
After recrystallization
fromabsoluteaalcoholpthe saltpartially melts at
hydroxide.
>
EXANIPLE 13
PREPARATIGN or 3-PHENYLcARBAMIno-4- (P-AMINO
'BENZENEJSUIJPHQNAMIDO) JANISOLE
10% aqueous solution of the sodium salt of 3
'amino-lle (,p~acetamino-benzene -'sulphonamido) -
:anisole is “mixed with'an equivalent amount ‘of
phenyl isocyanate, "and shaken in the "shaking
_machine until the'odorof phenyl isocyanate has
disappeared. 'I‘he’solution'is-?ltered to remove
anydiphenyl'urea‘which'has formed, and'is then
‘acidi?ed; ‘and theacetyl derivative, 3'-phenylcar
»160—.'162° C.,.then resolidi?es and decomposes .at
baniido-‘l- (peacetamino ibenzene-sulphonamido) 175° .0.
30 ‘anisole, separates ‘as ‘a granular powder. 'This
powder is then digested for about an hour with
a 50 % mixture ‘of 10 %' aqueous ‘hydrochloricacid
"(11) “PREPARATION For *3;(-P-AMINo-BENzENE;SuL
When-allthe acetylderivative has
been hydrolyzed,>a.clear solutionresults, which
. and alcohol.
NO) -'AmsoLE
;3.1 ,g.'.'3.-amino-4-. (?-Idiethylamino~ethylamino) - 35 is then cooled and neutralized to about pH 6 by
aniscle'is mixed with‘23 g..p-.acetamino-benzene
the-addition of aqueous sodiumrhydroxide, where
s1ilpho‘nyl chloride, and the , mixture is treated
uponthe ‘product, 3»-1,p'henylcarbamido‘ - “4i - .(p
'amino-benzeneesulphonamido) '- :anisole, sepa
withflli .g. . pyridine, .whereupon .the .mixture be
.comes hot.and forms athicksolution. Afteran
rates :as. a granular 1 powder.
'hour,.abo1it l'3.00..cc...of water ..is added, and an 40 ICompounds embodying a ‘substituted phenyl
. acetyl . derivative, .3- (p-acetaminoébenzene - . sul
~carbamido radical may the obtainedin the same
.phonamido) eé-(?ediethylamino
-
ethylamino) —
‘manner, ‘using the correspondingly?substituted
phenyl 'isocyanate reactant.
anisole, separates .as ,a gpasty .soli'd. After thor
oughly washing with water, this product ‘is .hy
.drolyzed.bydigeSting for. about. anghour w-ith'_200 .45
cc. 111% aqueoushydrochloric acidito .Whichabout
100 cc. alcohol has been added. The clear/solu
tion which forms is boiled, lastly with decoloriz
ing carbon ?ltered, and‘. neutralized with aqueous
.EXAMPLE l4
l-(a) PREPARATION or 2,4?111-(9-‘A0ETAMIN0-BEN
=ZENE4SULPHONAMIDO) —ANISOLE
'25 g. ..2,;4-.diamino-anisole dihydrochlori‘de :and
sodium hydroxide to about pH '6, whereupon the $50 ‘27.5 g. p '- acetam'ino-benzene sulphonylchl'oride
are mixed in a mortar, and 40 cc.' pyridine is
product, '3-‘(p-amino-'benzene-sulphonamido) :4
added nthereto. .A .:deep:red liquid dorms and
(/3-diethylamino=ethylamino) =ariisole, ‘ separates
as a granular solid; and on recrystallization ‘from
50% .alcohol,“the-product.ishbtained as a .buff
i. colored -.crystalline . solid.
EXAIVIPL'E 12
“PREPARATION 1 OF ‘3- (IMAMINO-BENZENE*SULPHON
ism-n0) ‘4-CARBA-MIDO-ANISOLE
'¥3-’nitro~¢l-amino anisole is ‘dissolved in glacial
acetic acid and-‘an equivalent quantity ‘of ‘?nely
‘divi‘ded "potassium v‘cyanate ‘is gradually added
thereto. “After-standing‘ two "'da'yathe solid prod
'uct,'13#nitro-¢l=carbamidoianisole, "is collected on
a‘?lter ‘pad, washe'diwith water;an‘d catalytically
hydrogenated in glacialacetic acid in‘the'presence
of .Adams’..catalyst. When theltheoretical volume
there is—,a-.slight.rise:.intemperature. ,The reac
tion mixture is heated on the steam bath ,for
“onelhalf hour, an'di25 ‘cc."50% “sodium hydroxide
".55 'isladded thereto. Theoily gob which settles to
‘the'bottom of the mortar is washed several times
‘with 10% hydrochloric acid, ‘decanting after
each washing. After standing 'for about one
hour, the oil becomes granular, and is ?ltered.
On'recrystallization'irom alcohol, ‘the product,
2,4 --- di-'(peacetamino-benzene-sulphonamido)
>-anisole,imeltsaat 2374-18" C. "(Fisher melting-point
*block) ;_C24l;2° ‘C. (uncorrected).
‘.(b) -PRERARATION 032,4 .DI-(PvAMINOéBENZENE
. SULPHONAMIDO) wANISOLE
'10- ‘g. "2,4 -- ’ di- (‘p-racetaminoebenzeneesulphon
of hydrogen’haslbeen taken_up,..the glacial acetic
amide) —anisole is hydrolyzed ‘with about 1125 .3 cc.
acid is removed in vacuo, the residue alkalinized
10% hydrochloric acid, a small amount of alco
A clear
~ with strong :saqueous =:so.dium Lhyclroxide, and rthe 110 hol being added 'to 'rprevent‘iforming.
product‘ taken :uprinether. r-After evaporationiof
theeethenthe product, B-aminQ-A-carbamidQ-an
solution ,forms?after heating about 40_minutes.
The solution .is cooled, and .majdejjus‘t alkaline ‘to
:isole ‘ris 'robtainedms .i'a {dark-colored semi-solid.
eWithout ."puri?cation, >lt. is =>ta~ken up :in ‘pyridine
Congo red; and'the precipitate,"‘2,4-“di'(p'-amino—
.benzene-sulphonamido) =anisole, .is :?'ltered, wand
:and ». treated ;with i the equivalent :quantity ..of ,;p- x175 -recry'stal1ized..fr0m :alcohol.
2,407,309
' 13
14
red. The product, 3 - (p-acetamino-benzene
EXAMPLE 15
(a) PREPARATION or 2,5 DI-(P-ACETAMINO-BEN
ZENE-SULPHONAMIDO) —ANISOLE
sulphonamido)44-benzylamino anisole separates
out as a light-brown crystalline material, and is
puri?ed bycrystallizing from equeous alcohol.
25 g. 2,5 diamino-anisole dihydrochloride is
(12) PREPARATION or 3-(P-AMINO-BENZENE-SUL
suspended in 250 cc. ethyl acetate and 100 cc.
PHONAMIDO) —4-BENZYLAMIN0-ANI50LE
10% sodium hydroxide is added thereto. The
base is extracted with‘ ether, and added to 27.5 g. _
: 15.3 g. 3 — (p »- acetamino-benzene-sulphon-.
p - acetamino - benzene —, sulphonylchloride sus
amido) —4-benzylamino-anisole is added to 150 cc.
10% hydrochloric acid mixed with 90 cc. of alco
hol, and the mixture is re?uxed'until all the
pended in 100 cc. ethyl acetate. The reaction
mixture is allowed to: stand in the ice box for
about three days, and the crystals formed are
solid dissolves (about 1/2 hour); It ‘is then
?ltered off and dissolved in 10% sodium hy
?ltered hot, and the cooled ?ltrate is made alka
droxide; and the solution is treated with acti
line to litmus with strong sodium hydroxide.
vated charcoal and ?ltered. The ?ltrate is then 15 The product, 3 - (p - amino-benzene-sulphon
made neutral with 10% hydrochloric acid. The
amido)—4-benzylamino-anisole, separates out as
pinkish precipitate formed, 2,5-di(p-acetamino
a red gummy material, and is washed with
benzene-sulphonamido)—anisole, is ?ltered off
water and crystallized from aqueous alcohol, and
and recrystallized from alcohol; it melts at 176-9°
C.
(uncorrected).
‘
-
is then a pale-pink crystalline material.
20
‘
(amino - benzene - sulphonamido) - aminophenol
(b) PREPARATION or 2,5 DI-(P-AMINO-BENZENE
SULPHONAMIDO) —ANISOLE
ethers (A) and other compounds (B) and (C)
~
may be obtained by the procedure of the fore
going examples, using the appropriate reactants.
The following additional compounds, inter alia,
20 g. 2,5 - di(p—acetamino—benzene-sulphone
amido) —anisole is boiled for one hour with 200 cc.
10% hydrochloric acid. The clear solution
formed is cooled, and made neutral to Congo
red with sodium hydroxide. The precipitate,
-
are thus obtainable:
2 - acetamino '- 5 - (p - nitro - benzene - sulphon
2,5 - di(p-amino-benzene-sulphonamido) —anisole
amido) —anisole
is ?ltered off and recrystallized from alcohol.
2 - acetamino - 5 —(p - amino —benzene - sulphon
amido) —anisole
' .EXAMPLE' 16
PREPARATION or 3,4-DI(P-AMINO-BENZENE-SUL
PHONAMIDO) —ANISOLE
Z-acetamino - 5 -(p-acetamino—benzene-sulphon
amido) —anisole
anisole
3-nitro-4-amino-anisole is condensed with p
carbamido)'-4
(ip-acetamino—benzene-sulphonamido) - anisole
[from
3 - nitro-4-(p-acetamino-benzeneesul
4 - (p-acetamino—benzene-sulphonamido)- ani
.
3-(2-nitro - 4 - methoxy - phenyl
the manner described in Example'i (a)—the re
phonamido) —anisole is then reduced to 3-amino
'
2-amino-5-(p-amino - benzene - sulphonamido) -
acetamino-benzeneesulphonyl chloride—e. g. in
sulting
‘
Manifestly, a large number and variety of other
3-amino-4-(p-acetamino-benzene-sul
phonamido)-anisole and 2-nitro-4-methoxy
40
phenyl isocyanate]
‘
3 —(2 - nitro—4-methoxy-phenylcarbamido) —4-(p
sole—e. g. in the manner described in Example
1 (c)—.the latter is condensed with p-acetamino
amino—benzehe-sulphonamido) —anisole
benzene-sulphony1 chloride to obtain 3,4-di(p
3- (2-amino-4-methoxy - phenylcarbamido) -4(p
acetamino-benzene-sulphonamido)—anisole, and
amino-benzene-sulphonamido) —anisole .
3-(p-amino - benzene - sulphonamido) —5-amino
the diacetyl‘compound is hydrolyzed-—e. g. in the
manner described in Example, 1 '(b)-—'to obtain
anisole
sole.
_
-
‘
I
‘ amido) —anisole
'
.
'
'
.
3-amino-5-(p-amino - benzene - sulphonamido) -
EXAMPLE 1’?
50
3- (p-amino .-- benzene-sulphonamido) - 4 ‘- (‘p-ani
(a) PREPARATION or‘ 3-(P-ACE'1‘AMINO-BENZENE
soyl-amino) —anisole [from' 3-nitro-4-amino
SULPHQNAMIDO) —4-BENZYLAMINO-ANISOLE
.
25 g. 3-_nitro-4f-amino-anisole is dissolved-by,
benzoyl - amino) - anisole
and '10 cc. of ‘benzyl chloride. The solution is
heated under a re?ux condenser for 12 hoursat
about 100° C. ; on cooling, crude 3-nit'ro-4-ben‘zyl
amino-anisole separates, out in the form of red
needles. It is puri?ed by recrystallizingfrom
aqueous alcohol, from which itsepalrates as bright
. ,
‘ '
i
’
I
’
[from
3 - nitro-“4
amino-anisole and, p-‘nitro-benzoyl chloride]
3 -‘ (p - amino - benzene - sulphonamido) - 4 —(p
amino-benzoyl-amino) —anisole
‘
3-diethylamino - 4 —(p - amino-benzene-sulphoné
60 1 ~ amido) —phenetole [from 3-diethylamino-4
> amino-phenetole, obtainable by reacting 3-;
diethylamino-phenetole with phenyl-diazonium '
chloride, and reducingrthe resulting azo corn- '
"
19.5 g. 3—nitroA—benzylamind-aniSole is‘ dis;
solved in 225 cc. ofv absolute alcohol, and hydro
genated in the‘. presence of Adams’ platinum
oxide‘ catalyst. “The solution changes from red
to colorless or pale yellow. The catalyst is then
‘pound with SllClz and HCll'
’
r
r l
,
2 - (c # cliethylamino-ethylamino) 4 4' —(p # amino
' benzene-sulphonamido) -anisole
2 —(e - diethylamino-ethylamino) - 5 —(p - amino- '
?ltered off, and the alcoholic ?ltrate is concen
trated under reduced pressure to give crude 3
benzene-sulphonamido) —anisole
3 - (p - amino - benzene-sulphonamido) —4- (lb-hy
amino-4—benzylamino-anisole as a red syrup.
droxy-?’—chloro-iso-propylamino) —anisole
17 3—amino-4—benzylamino-anisole is dissolved
in 20 cc. pyridine, and 17.6 p-acetamino-benzene
sulphony1 chloride is added thereto in small por
tions. The syrupy liquid is allowed to stand for
3 - (p-amino - benzene-sulphonamido) —4-(p-hy
droxy - ?’- diethylamino-isopropylamino) —ani
sole [by replacing the chloro radical in the
about 24 hours at room temperature, after which .
it is diluted with water and acidi?ed to Congo
anisole and p-anisoyl chloride]
3- (p-amino-benzene—sulphonamido) —4- (p-nitro
. warming in a'mixture of_ 501cc. of benzyl alcohol
red needles melting at 105°C.
.
3-acetamino —5 -(1p-acetamino—benzene-sulphon
3,4 - di(-p - amino-benzene—sulphonamido)—ani
‘75 I
immediately preceding compound with a di
ethylamino radical in the conventional manner]
2,407,309
15
1'6
N2-methy1-3-methoxy-o-phenylene-diamine
3-- (pe'amino-benzene~sulphonamido) -"4'-"[N-'(:5
diethylamino-pentyl-z) l -amino-‘anisole
3 -'(p - amino - benzene-isulphonamido) - 4 -Val1yl
amino-anisole [from 3-nitro-4-al1ylamino
anisole, obtainable by reacting 3-nitro-4
amino-ani'sole 'with allyl bromide]
3 - (p-amino-benzene-su1phonamido) - 4 - propyl
ramino-anisole [from S-amino-é-propylamino
anisole, obtainable by catalytic hydrogenation
1 of
3-nitro-4-allylamino-anisole]
10
.
3 -- amino - 4 - [N -(p - acetamino - benzene — sul
phonyl) -& N'— (p-diethyl-amino-ethyl) 1 —amino
.anisole [by dissolving 3-amino-4—(p-acetamino- '
vbenzene--sulphonamido) -anisole in
, ‘excess of aqueous
a slight
alkali and boiling
3-methoxy-N'-pheny1-p-phenyleneediamine
4-ethoxy-mephenylene-diamine
4-cyclohexyloxy-m-phenylene-diamine
4-phenoxy~o-phenyleneediamine
2-ethoxy-p-phenylene-diamine
z-butoxy-Né-phenyl-p-phenylene-diamine
4-methy1-G-nitro-m-anisidine
6-methyl-2—nitro-m-anisidine
6~methyl-5-nitro-m-anisidine
5-methyl-6-nitro—o-anisidine
5-methoxy#m-phenylene-diamine
3-methoxy-o-phenylene-diamine
2-methoxy-p-phenylene-diamine
3-nitro-4-diethylamino-anisole (from '3-nitro-4
with
‘iodo-anisole and diethylamine)
. c-diethylamino-ethyl chloride]
A derivative of 3-amino-é-(p-amino-benzene
It is further obvious that (amino-benzene
,sulphonamidm-anisole in which both R and
sulphonamido)-aminophenol ethers which con
R4 are methane sodium sulphinate radicals
A derivative of 3-amino-4-(p-amino-benzene 20 tain one or more free amino groups may be con
verted into a variety of acyl derivatives other
sulphonamido) -aniso1e in which R is a methane
than those disclosed hereinbefore, inter alia,
sodium sulphinate radical
glycolic, thioglycolic, and malic acid derivatives.
A derivative of 3-amino-4-(p-amino-benzene
Thus, for example, 3~glycolyamino-4-(p-acetam~
sulphonamido) -anisole in which R4 is a meth
ino—benzene~sulphonamido) -anisole' may be ob
ane sodium sulphinate radical
25
tained
by fusing 3-amino-4-(p-acetamino-ben
A derivative of 3-amino-4-(p-amino-benzene
zene-esulphonamido)-anisole with an equivalent
sulphonamido) —anisole in which both R and R4
quantity of glycolic acid.
area-ethane sodium sulphonate radicals
The invention ‘is not to be construedas in ‘any
A derivative of B-amino-ll-(p-amino-benzene
sulphonamido)—aniso~le in which R is an 30 sense‘ restricted to the foregoing’spec'i?c examples,
compounds, reactants, procedures or steps, but
may be variously otherwise embodied within the
scope of the appended claims.
su1phonamid0)-anisole in which R4 is an
We claim:
-a-ethane sodium sulphonate radical
1. A compound of the general formula
35
m-ethane sodium sulphonate radical
'
A derivative of 3-amino-4-(peamino-benzene»
Manifestly, also, compounds wherein the amino
group
R\N_
40
/
RI
wherein'R' represents a member of the group
consisting, of hydrogen, hydrocarbon, dialkyl
and the sulphonyl group are meta or ortho to each
amino-substituted-hydrocarbon, and > acyl radi
other may be obtained by the procedure of the
cals.
foregoing examples, using the appropriate meta
or ortho nitro-benzene-sulphonyl halide, alkyl- ",. . L:
amino-benzene-sulphonyl halide,‘ or acylamino
NHzOSQENHOO-(iower alkyl)
benzene-sulphonyl halide; and compounds where
in either or both of the benzene rings contain
further substituents—which compounds it’ should
be noted, are comprised by the genus (amino 50
benzene-sulphonamido)-aminopheno1
'
2. A compound of the general formula
ethers—
'H
may be obtained by using the correspondingly
substituted nitro-amino-phenol ether, alkyl
amino-amino-phenol ether, or acylamino-amino
phenol ether and/or the correspondingly-sub
stituted nitro-benzene-sulphonyl halide, alkyl
amino-benzene-sulphonyl halide, or acylamino
consisting of hydrogen, hydrocarbon, dialkyl
amino-substitutedhydrocarbon, and acyl radi
benzene-sulphonyl halide in the procedure of the
do) -aniso1e.
wherein R4 represents a member of the group
cals.
p—Methylamino-benzene-sulphonyl chloride
p-Diethylamino-benzene-sulphonyl chloride
,
,
4. 3-amino-4-(p-aminoebenzene -, sulphonami
foregoing examples.
Among'other reactants utilizable in the pro
cedure of the foregoing examples for the prepa
ration of ‘the compounds of this invention are:
‘
3. 3-amino-4- (p~amino-benzene ¢ sulphonami
60
do)_-'phenetole.'
_
'
i
5; 3-phenyl'carbamido-4 -(p - amino - benzene
sulphonamido) -anisole.
‘
.
WILLIAM A. LOTT.
FRANK H. BERGEIM.
65
KATHRYN A.‘ LQS'EE.
‘
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