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Патент USA US2117260

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Patented May 10, ‘1938
2,117,260
UNITED STATES
PATENT OFFICE I
2,117,280
SUBSTITUTED
P - AMINO - BENZENE - SUL
PHONAMIDES AND PROCESS OF PMDUC
ING THEM
Elmer 11. Stuart, Indianapolis, Ind., minor to
Lilly and Company, Indianapolis, Ind., a
corporation of- Indiana
No Drawing. Application June 26, 1937,
Serial No. 150,545
10 Claims. (Cl. 260-106)
My invention relates to substituted p-amino
end, preferably, I boil a slightly acidi?ed aqueous
benzene-sulphonamides, particularly p-mandelyl
solution of the p-acetylmandelylamino-benzene
sulphonamide for several hours, to remove the
acetyl radical. The reaction is apparently as
follows:
amino—benzene-sulphonamide and its intermedi
ate p - acetylmandelylamino - benzene - sulphon
5 amide, and to the procws of producing them; both
a
(I? H-
lee-(5Q
t
(2)
10
0=c-cn,
H 0 H
I'M-i0
in
+H,o->
(is
+ o=c~om
10
(Acetic acid)
0: I-NIL
O=B—'NH!
15
15
(g-Aoetylmandelylamino
enzone-sulphonamide)
(p-Mandelylamino
benzene~sulphonamide)
in their racemic and in their optically active forms.
The - p-mandelylamino - benzene-sulphonamide
This new compound, p-mandelylamino-ben-
thus obtained, when recrystallized from alcohol,
20 zene-sulphonamide, in its raoemic form as well as
in its d and 1 forms, on oral administration, has
is a white crystalline solid, which melts at- about 20
232° C. corrected. Assay for sulphur indicates
excellent protective and curative properties
against various infections, including urinary infections; and its toxicity is low.
the correctness of the formula given.
Both my intermediate product and my ?nal
The intermedi-
product, p - acetylmandelylamino - benzene - sol
25 ate product, p-acetylmandelylamino-benzenesulphonamide, also has therapeutic properties.
phonamide and p-mandelylamino-benzene-sul
phonamide respectively. are sparingly soluble in 25
While variants of my method may be used in
preparing p-mandelylamino - benzene- sulphonamide, the method I prefer is as follows:
30
p-Arnino-benzene-sulphonamide is treated, in
water, and more soluble in alcohol; the inter~
mediate product being soluble in ethyl alcohol to
the extent of about two parts per hundred, and
the ?nal product to the extent of slightly less
solution or suspension in a non-polar solvent,
than one part per hundred. Both can be admin
such for instance as chloroform or benzene, with
acetylmandelyl chloride (a method for preparing
which is described in Organic Syntheses, volume
35 4, page 1, published 1925 by John Wiley and Sons,
Inc., New York); and the whole is then treated
to drive o? the solvent. This produces a reaction
as follows:
H
I’
*0
+
‘5
o
H
"
lei-60
t
o H
(1)
istered orally, most conveniently in tablet form,
in the treatment of various infections, and are
found to be effective.
The following is an example of the process of
manufacturing my new product:
To about 70 grams of p-amino-benzene-sul
phonamide are added about 500 cc. of benzene,
or-tLiz-O --->
o=c-oni
o=o-0Hi
o= —-NH.|
(p-Amlno-
50 benzene-sulphonsmldo)
‘
(Acetylmandelyl
chloride)
0: —-NH,
(p-Acetylmandclylamlno
benzene'sulphonamide)
The p-acetylmandelylamino-benzene-sulphon-
to form a suspension; and then there is added
amide is a new product, an intermediate in my
about 71 grams (about a molecular equivalent or
present invention although it also has valuable
properties in combating infections. when ?rst
55 produced this is a light-tan-colored powder, but
on recrystallization from alcohol it is obtained
slightly less) of acetylmandelyl chloride.
The
mixture is boiled on a water bath until about half
of the benzene or slightly more than half is 55
evaporated; and then substantially all the re
in the form of white crystals, which melt at
maining benzene is removed by evaporation in
187.5-189.5° 0., corrected.
In order to obtain my ?nal product, I remove
so the acetyl group in any suitable manner. To this
vacuo. This leaves a light-tan-colored solid,
which is the p-acetylmandelylamino-benzene~
sulphonamide, my intermediate product. If de
2
2,117,260
sired, this intermediate product may be purified
by recrystallization from alcohol; but puri?ca
which compound melts at‘ about 1875-1895‘ C.,
tion at this stage is not necessary unless it is
desired to use this intermediate product as the
more soluble in alcohol.
?nal product.
and is sparingly soluble in water and slightly
3. The new compound, p-mandelylamino-ben
zene-sulphonamide, which has the following
structural‘ formula:
,
To produce the final product, the intermediate
product obtained as above, whether or not it
HO
has been subjected to recrystallization, has added
iii(50
to it about 1200 cc. of water and about 50 cc.
10
of concentrated (36%) hydrochloric acid. These
amounts of water and hydrochloric acid are not
critical. The mixture obtained is re?uxed for
10
several hours, conveniently about four hours, and
then cooled to room temperature. In such re
15 ?uxing, there is usually at ?rst a considerable
O: —NH:
3
foaming, with the particles'cf solid matter largely
in and on the foam; but as the re?uxing con
tinues the'foam disappears, and the solid particles
which compound is sparingly soluble ‘h water and
tend to distribute themselves more or less uni
slightly more soluble in alcohol.
20 formly through the liquid, which I think is an
indication that the reaction has been substan
tially completed. On cooling, this solid matter
zene-sulphcnamide set forth in claim 3.
arated from the liquid by decantation and/or
25 ?ltration.
This solid matter is of a light-tan
color as thus ?rst obtained; but on recrystalliza
tion from alcohol it is obtained in the form of
-
.
ylamino-benzene-sulphonamide, which consists
in causing p-amino-benzene-sulphonamide to
react with acetylmandelyl chloride in a non
I
polar solvent.
7. The process of producing p-mandelylarnino~~
benzene-sulphonamide, which consistsin caus
Whether my intermediate product and my ?nal
30 product are of the racemic (d1) form, or of the
levo form or the dextro form, may be controlled
ing p-amino-benrzene-sulphonamide to react
with acetylmandelyl chloride in a non-polar sol
vent 'to produce peacetylmandelyiamino-benzene
suiphonamide,‘ and treating. the p-acetylmandel-~
ylamino-benzene-sulphonamide to remove the
as desired by selecting the initial .acetylmandelyl
chloride of the racemic or of the levo or the
dextro form; for the form of my intermediate
35 and final products corresponds to the form of
that acetylmandelyl chloride in respect of op
tical rotation. All theseforms of my intermedi
ate product and of my final» product are ef
?cacious in the treatment of infections.
acetyl group therefrom.
~
.8. The process o‘fproducing p-mandelylamino- . _
ben‘zehe-sulphcnamidd?hich consists in treating
p-acetylmandelylamino-fbenzene-sulphonamide to
‘1 claim as my invention:
remove the acetyl group therefrom.
1. The substituted p-amino-benzenersulphon
V
._
40
9. The process ‘of‘producing p-mandelylamino
benzene-sulphonamide’, which consists in causing
amides, in which a hydrogen atom of the p
amino'g'roup is replaced by a radical of the class
p-amino-benzene-sulphonamide to react with
acetylmandelyl chloride in a non-polar solvent
consisting of the mandelyl and the acetyl-man
to produce p-acetylmandelylamino-benzene-sul 45
phonamide, and boiling the p-acetylmandelyl
delyl groups.
2. The new compound, p-acetylmandelylami
no-benzene-sulphonamide, which has the fol
lowing structural formula:
50
e
5..The dextro form of the p-émandelyllmmo
benzene-sulphonamide set forth in claim 3.
6. The process of producing p-acetylmandel
tends to settle to the bottom, and may be sep
white crystals.
.
, 4. The levo form of the p-mandelylamino-ben
amino-benzene-sulphonamide so obtained in a
slightly acidulated aqueous solution to remove the
acetyl radical and thus produce the desired p
ieiaié <3
mandelylamino-benzene~sulphonamide.
.
50
1G. The process of producing p-mandelylami
~su3phona1nide, which consists in boil
noubenzei
M
icle in a 51.1
"'
'
lylainino-benzene-sulphonam
a. 9 ?ulated aqueous solution to re
move the ace yl radical and thus produce the 55
desired p-mandelylaminoebehzene-sulphonamide.
‘
H. STUART.
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