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Патент USA US2111913

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My present invention relates to a new process
tor the manufacture of. sulphanilamide and, more
speci?cally, to a process by which sulphanilamide,
or p-aminobenzene sulphonamide, may be manu
s lectured irom cheap and readily available raw
materials, such as the lay-products from the man
uiacture oi saccharin.
v
.
in;
.
in i935, Damask (Deutseh. Med. ‘Wochsch: 61,
use, 1935) described the remarkable protection
W atlorded to mice infected with virulent strains of
hemolytlc streptococci by injections of azo dyes
containlne the sulphonamide group para to the
ace linkage. However, Colebrooh, Buttle, Comb,
éO’hleara and Kenny (Lancet, 2, 1319, 1323, Dec.
315 5, 1936) found that these dyes have no in
hihiting or bacteriostatic activity on hemolytic
streptococci in vitro. By reduction with mag
ncsluinpowder in vacuo, or with sodium form
aldehyde sulphoirylate (Lona and Bliss, Journal
of the American Medical Association, vol. .108,
No. 1, pg. 33), these azo dyes acquired an inhibi
tory effect in vitro comparable to that of the
compound p-aminobenrene sulphonamide, here
obtained. The yields of this process are not sat
isfactory and the product obtained is usually con
taminated by impurities and by-products, which
are chemotherapeutically inactive.
I ?nd that sulphanilamide may he obtained in
an exceptionally pure state and in quantitative
yield by submitting henzamide-p-sulphonarnide
to a Hoi‘mann reaction. As is well lrnown to all
persons skilled in the art, the Hoimann'reacticn
involves the conversion of compounds oi‘ the type 10
REONI-lz to compounds ‘of.’ the type litlt'l’l-ls (where .
R represents an alkyl or an aryl group) by react-i
insthe former with a halogen in the presence oi
an excess oi tree allrali, or with the ‘chemical
equivalent thereof, an ‘ aqueous solution of an 15'
alkaline or alkaline earth hypohalite in the pres
ence of free alkali. The reaction'may he ‘reps-e7
sented ‘by the following equation:
C ONE):
NHa
' +No0 common»
' +Nsoi+uao 0:;
inatter referred to as sulphanilamide. They con
cluded, therefore, as did Treiouel, Nitti and Eovet
(@olnntes iendus Soc. Biol. 120, 756, 1935) that
these aso sulphonamide dyes have no activity per
se but are similarly reduced ,in vivo to the chemo
s 0mm
'
o emu,
‘the conversion of henaamide--p~sulphonamide
to sulphanilan'llde proceeds smoothly under the
usual conditions of the Hermann reaction. Thus,
therapeutically active principle, sulphanilamide. ~ benramide~p-sulphommide (1 mol.) may heidis
30
Numerous subsequent reports have con?rmed
this conclusion and, at the present time, sulphanil
amide is mine widely used for peroral and paren
teral administration to humans in cases of hem
olytic streptococcus conditions such as erysipelas,
septicemia, puerperal sepsis, ~ osteomyelitis of
streptococcic
origin,
peritonitis,
soarlatina,
streptocmcus memnsitis, Ludwic’s angina, “ otitis
media, etc,‘ as well as in pneumonia, especially
where the causative organism is pneumococcus
40 type m. A'tremendousnew ?eld for the use of
sulphanilamide has recently'alsobeen opened by
the remarkable cures obtained with its use in the
treatment of gonorrhea (Bees and Colston, Jour
ml of the American Medical Association, vol.
45 lot, No. 2, pg. 1855, 1937.) .
, Heretoi’ore, sulphanilamide has been manu
factored exclusively by the process originally de
scribed by Gelgno (Journal fur ‘Praktische Chemie,
(2), vol; 77, pg. M2) or by‘ minor modi?cations
_ 50 thereof. y'i'his process involves reacting N-acetyl
solved in aqueous caustic soda (2 mole) and sodi
um hypochlorite (1"mol.) added to the resultant
solution. alternatively, henzamiole-p-sulphom
amide (l moi.) may be dissolved “in aqueous
caustic soda (ll mols) and chlorine has (1 mol.) '
missed into the resultant solution. Alternatively, » 35
henzamlde-p-sulphonamide (1 mol.) may be re
acted with a solution of chlorine gas (1 mol.) in
aqueous caustic soda (t mols). On neutralizing
the reaction mixtures in each case after the re- '
moval oi? all the available chlorine, a quantita 40
tive yield of sulphanilamide may be obtained. A
sinylereorystallization from water yields a prod- 7
not suitable for human consumption.
It is not the purpose of mm invention to’ limit
the manufacture oi.’ sulphanilamide to benzamide 45
pvsulphonamide obtained from any speci?ed raw
materials. Obvious means of preparing this inter
mediate will occur to any person smiled in the
art. However, the by-products obtained in the
manufacture‘ of saccharin may cheaply and sim 50
or N-benzyl-sulphanilic acid with phosphorus ' Jply he convertw. to benzamide-pesulphonamide
and are, therefore, of importance in this process.
v‘pentachloride, converting the resultant N-acetyl
or N-loenzyl-‘sulphouyl chloride to the correspond- '
ing amide and subjecting the letterto an acid or
_ 5s alkaline hydrolysis, wherebysulphanilamide is
_ German Patent #353717 describes the prepara
tion of benzamide-psulphonamide from benzoic- '
p-sulphonic .acid, or a salt thereof, by reacting
2
I
-
2,111,918
the latter with phosphorus pentachloride to form
and illustrate this invention but in no way'limit
benzoyl chloride-p-sulphonylchloride, then with - it to the reagents, proportions or conditions de-e
ammonia. to form the diamide. Benzoic-p-sul
phonic acid may readily be obtained by the oxidaé
5 tion of toluene-p-sulphonic acid or toluene-p
scribed therein.
.
'
'
'
'
Example I
20.0 kgs._of.benzamide-p-sulphonamide. is dis- 5
solved ‘in 160.0 liters of a 5% (‘1.3” Bé.) solution
of caustic soda in the cold. and 55.0 liters of 14%
charin.
.
>
German Patents #96,125 and #103,298 describe sodium hypochlorite solution is added. The so
10 the- preparation of benzamide-p-sulphonamide lution is .then heated gradually to 40° 0., and sul 10
phur dioxide is passed into it until a negative re‘
'by the anfi'nonolysisv3 of ethyl benzoate-p-sul
phonyl chloride. The latter may be obtained by \ action to potassium iodide-starch paper is ob
ethyiating benzoic-p-sulphonic acid and reacting tained. The reaction mixture is then neutralized
to' phenolphthalein with 420 Bé. sulphuric acid,
the resultant ester with phosphorus pentachlo
sulphonyl chloride (Remsen, Annalen, 1'78, 284,
290), by-products of the manufacture of sac—
15 ride.
and the copious precipitate of sulphanilamide'15
>
Asa starting point in the synthesis of benz
amide-p-sulphonamide, I prefer to use p-toluene
sulphonamide. on oxidation (alkali dichromate
‘in acid solution, alkali permanganate in acid
which forms on standing overnight is ?ltered off.
After a single recrystallization from water, 15.8 .
to 16.4 kgs. of pure sulphanilamide is obtained
(92% to 95% of the theoretical, based on the
benzamide-p-sulphonamide consumed).
20
Example II
benzoic acid are obtained (Remsen, Annalen, 1'18, ,
17.5 kgs. of technical p-toluene sulphonamide
297). p-Sulphonamidobenzoicacid is then es
is suspended in a cold solution of 50.0 kgs. of po
teri?ed in the usual manner, preferably by the tassium
dichromate and 75.0 kgs. of 66°, Bé. sul
20 or alkaline solution, alkali ferricyanide in alka
line solution) good yields of p-sulphonamido
25 use of an alkylating agent, such as a dialkyl sul
phate, an alkyl halide, an alcohol in the pres
ence of a condensing agent such as dry hydro
chloric acid gas or a dehydrating agent such as
concentrated sulphuric acid, etc."
30
After ashort time, separation of. p-sulphonamido
benzoic acid commences and at the end of two
hours,
the entire reaction mixture is -a thick 30
verted to benzamide-p-sulphonamide by am-.
benzoate with an excess of dry ammonia gas at
normal orincreased pressure in an autoclave, a
35 quantitative yield of benlzamide-p-sulphonamide
is obtained. By reacting ethyl-p-sulpho‘namido
- ’ benzoate with concentrated aqua ammonia at or
dinary temperatures, benzamide-p-sulphona
mide is obtained in yields of 65% to 85% of the
' 4o theoretical, depending on the concentration of
. the ammonia and the reaction time.
'
commences and the amide goes into solution.
Alkyl-p-sulphonamidobenzoate may be con
monolysis. By reacting ethyl-p-sulphonamido
-
phuric acid in 125.0 liters of water. The mixture 25
is warmed slightly and mixed until the reaction
The re
maining 15% to 35% of the ethyl-p-sulphon
amidobenzoate‘is hydrolyzed to the ammonium
salt of -sulphonaminobenzoic acid, which ‘is
45 readily s luble in water and may thus be sep
arated from the substantially insoluble benza
mide-p-sulphonamide by ?ltration and returned
to the process.-
'
One of the di?iculties encountered in the pres
50 cut processes of manufacturing saccharin is the
separation of the para and the ortho isomers of
the crude toluene sulphonyl chloride. If this
separation is not attempted but the combined toluene sulphonamides are converted to the corre
55 sponding ethyl sulphonamidobenzoates; as de
scribed above, an excellent means is provided of
obtaining both saccharin and benzamide-p-sul
phonamide in a single operation.
’ The conversion of ethyl-o-sulphonamido-ben
o0 zoate to saccharin by reaction with ammonia is
rapid and quantitative (German Patent #103,
298). The combined‘ ethyl sulphonamidobenzo
ates are reacted with aqua ammonia, and the re
action mixture is then diluted and ?ltered from
65 the insoluble benzamide-p-sulphonamide. The
?ltrate now contains the ammonium salts of sac-
charin and p-sulphonamidobenzoic acid in so1u~
. tlon. Thesaare separated by fractional precipi
tation with mineral acid, as described in German
70 Patent #64524. p-Sulphonamidobenz‘oic acid
precipitates out ?rst, is ?ltered of! and returned
to the process. Saccharin-then precipitates out
*“"*"*on~furtheracidi?cation, in- good, yield and in a
state of great purity.
magma. The heating is now,discontinued, the
reaction mixture is cooled to room temperature
and ?ltered. The precipitate of p-sulphonami
dobenzoic acid on the ?lter is then thoroughly
washed until the washwater is free of chromium. 35
The ?lter cake of p-sulphonamidobenzoic acid
is now dissolved in’ 80.0 liters of 5% (.7.3°~ Bé.)
solution of caustic soda and 15.4 kgs. of dlethyl
sulphate is added. Thef mixture is stirred until
the diethyl sulphate has. completely disappeared 40
and for an ‘hour thereafter.’
I »
The precipitate of ethyl-p-sulphonamidoben
zoate is now ?ltered 01! and added to 50.0 liters
of 27° Bé. aqua ammonia. After standing for 24
hours at room temperature, 100.0 liters of water 45
is added, and the precipitated benzamide-p-sul
phonamide is ?ltered on’. On acidifying the ?l
trate with 42° Bé. sulphuric acid, p-sulphonami
vdobenzoic acid is precipitated, ?ltered on‘, and returned to the process.
1
'
50
The benzamide-p-sulphonamide thus obtained
is converted to sulphanilamide as described in
ExampleI.
.
.
Example-III
J
,
22.0 kgs. of technical p-toluene sulphonamide is
dissolved in-12.5 kg. of 38% (35.2” Bé.) caustic
soda and 60.0 liters of water at a temperature not
exceeding 35° 0., and 40.0 kg. of potassium per
manganate ‘is added to the solution, with con- my
stant stirring in the course of three to four hours.
The temperature should not be allowed to rise
above 35° C. (lining the addition of the per—
manganate. Stirring is continued for three hours
after all the permanganate has been added and 05
- the reaction mixture is'then ?ltered or cen
trifuged. The precipitate- of manganese dioxide
is washed with 5011' liters of water and the ?ltrate
and wash water are combined.
'
42° Bé. sulphuric acid is added to the combined. 70 “
solution until the reaction is faintly acid to Congo
red. About 5.0 kgs. of unchanged p#toluene sul
phonamide is precipitated, ?ltered oil! and re- 2
turned to the process. ‘To the filtrate is added
75 ‘The following examples are intended to de?ne‘ 715.4 kgs. of diethyl sulphate.v The ‘mixture is 75
3
2,111,913
~ stirred until the diethyi sulphate has completely : . From 100.0 kgs. of mixed toluene sulphon~
amides, the yields are 50.7. kgs. of saccharin and
disappeared, and for an hour thereafter.
31.4 kgs. of salphanilamide.
,
v
1
- The precipitate of ethyi-p-sulphonamidoben
In the preceding examples, the amount used of
zoate thus obtained is converted to benzamide-p-'
.u
alkylating agent, e. g. diethyl sulphate, may be
decreased to substantially half ‘of that indicated
Example IV
by increasing the reaction time 'and temperature.
Having. described my invention, what I claim
10.0 kgs. of toluene is added in the course of
four hours to 15.0 kgs. of chlorsulphonic-acid and desire to protect by Letters Patent is:
1. A process for the manufacture of sulphanii 10
at —5° C. The mixture is then‘ stirred for two '
hours at —5° to —10° C. and. poured on 10.0 kgs. amide which comprises submitting benzamide
p-sulphonamide to a Hofmann reaction.
of ice and 10.0 kgs. of water.
2. A process for the manufacture'ot sulphanii
The resultant mixture of 10.0 kgs. of o-toluene ‘
sulphonylchloride' and-7.5 kgs. of p-toluene sul _ amide which comprises reacting benzamide-p
phonyl chloride is' decanted from the aqueous sulphonamide with a halogen in the presence of
sulphonamide as described in Example 11. ‘
layer and added to 15.0 kgs. of 27° Bé. aqua am
monia in the course of four hours. The mixture
alkali metal hydroxide.
I »
'
3. A process for the manufacture of. sulphanii
amide which comprises reacting vbenzamide-p
' is stirred at a temperature of 30°~35° C. for two
hours, washed free of ammonium chloride with ‘suiphonamide with an alkali‘ metal hypohalite
20
'in the presence of an alkali metal hydroxide.
20 5.0 liters of water and ?ltered. There is thus ob
tained about 14.0 kgs. of a mixture ‘containing
57% of o-toluene sulphonamide and-43% ‘of p
toluene sulphonamide. _
_
.
17.5 kgs. of the mixture of toluene sulphon
25 amides is treated as described in Example 11.
The ?ltrate from the precipitate of benzamlde
4. A process for the’manuiacture of- sulphanil- . ' amide which comprises reacting an ester of p-‘sul- ,
phonamidobenzoic- acid with ammonia and sub
mitting the resultant benzamide-p-sulphonamide
to a Hofmann reaction. .
'
'
25'
5. A‘ process for the manufacture of sulphanii-'
p-sulphonamide is fractionally precipitated with ~ amide which comprises reacting ethyl-p-sulphon- I
42° Bé. sulphuric acid as described in German amidobenzoate with ammonia and submitting the
Patent #64524. p-Sulphonamidobenzoic acid is Y resultant benzamide-p-sulphonamide to'a Hof
30
precipitated ?rst, ?ltered 011 and returned to the
mann reaction.
_
..
>
'
6. As a step in a process for the manufacture
.of sulpanilamide, the ammonolysis-ot an ester of ‘ precipitated.
The benzamide-p-sulphonamide thus obtained p-sulphonamidobenzoic acid.
_
v
.~
JONAS KAMLE'I'.
" is converted'to sulphanilamide ‘as described in‘ ‘
process.
On further acidi?cation, saccharin, is
- 35 Example I.
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