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Патент USA US3075022

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United States Patent O??ce
Patented Jan. 22, 1963
2 .
in excellent yields and with very good purity when per
forming the reaction of an arylsulfonyl urea with an al
Schatfhausen, Switzerland, assignors to Cilag-Chemie
kylamine in a ketone of a boiling point of approximately
90-120“ 0., preferably 100—120° C., at a molecular ratio
of sulfonyl urea to alkylamine of 1:1.2, care being taken
that the ammonia which is split off is removed from the
Limited, Schaithausen, Switzerland, a Swiss company
No Drawing. Filed Apr. 5, 1960, Ser. No. 20,034
reaction mixture as quickly and as completely as pos
Karl Koehei, Neuhausen am Rheinfall, and Robert Egli,
Claims priority, application Switzerland Apr. 7, 1959
7 Claims. (Cl. 260-553)
As already mentioned, aliphatic ketones boiling at tem
10 peratures of between 100 and 120° C. have proved to be
advantageous solvents. The possibility that the reaction
promoting in?uence of the aliphatic ketones is in any
way connected with the intermediary formation of keti
The present invention relates to a process for the pro
duction of Nl-arylsulfonyl-Nz-alkyl ureas, whereby aryl
signi?es a phenyl radical, a lower alkylphenyl radical, a
lower alkoxyphenyl radical, a halogenophenyl radical, or
a p-aminophenyl radical, and alkyl is an alkyl radical 15
containing from 2 to 8 carbon atoms.
N1-phenyl-, alkylphenyl-, -alkoxyphenyl- and -halo
genophenyl-sulfonyl-N2-alkyl ureas have been known for
(R: lower alkyl radicals; alkyl: an alkyl radical contain
some time (cf. British Patents Nos. 808,073, 808,072, and
808,071, Austrian Patent No. 196,413, and Swiss Patents 20 ing from 2 to 8 carbon atoms), cannot be excluded, but
has not been proved.
Nos. 331,999 to 332,007).
It is advantageous to choose as solvent a ketone which
It is also known from these patents to produce such
is little or practically insoluble in water. After termina
Nl-arylsulfonyl-Nz-alkyl ureas by reacting N-arylsulfonyl
tion of the transamination, the resulting Nl-arylsulfonyl
ureas with alkyl-amines (cf. Swiss Patent No. 332,005).
This process is called the transamination process by the 25 Nz-alkyl urea can be brought into solution in the aqueous
phase by the addition of an aqueous solution of an alkali
chemist skilled in the art.
hydroxide, While the ketone, which contains various im7
Repetition of the examples of Swiss Patent No. 332,005
purities, is separated oif. Thus, an additional puri?ca
applied to the production of Nl-p-tosyl-Nz-n-butyl urea
tion of the end product is obtained.
gives when working without diluent a yield of 2.5%, and
As ketones complying with the above requirements
when working with o-dichlorobenzene as diluent, which is 30
shall be mentioned: methyl isobutyl ketone, methyl-n
proposed in this speci?cation, a yield of 5%.
propyl ketone, methyl secondary butyl ketone, diethyl
Of course, such yields render impossible a technical
ketone, ethyl isopropyl ketone, etc.
application of this process. It was subsequently suggested
It is also possible to use a mixture of various ketones,
to convert Nl-aryl-sulfonyl-Nz-acyl ureas into their salts
by means of alkylamines and to heat the resulting salts 35 such as for instance a higher and a lower boiling ketone,
and to thus adjust the boiling point to the desired height.
to temperatures exceeding 100° C. (cf. Austrian Patent
The fastest possible removal of the split otf ammonia
No. 195,436 and German‘Patent No. 1,043,318). Better
can be accomplished in various manners known to the
yields can in fact be obtained with this process; it has,
chemist skilled in the art. Since the reaction is carried
however, the disadvantage of requiring one step more
through with the ketone at boiling point,‘it is necessary
than the simple transamination process.
to provide the reaction kettle with a cooling device. The
' N1-p-aminophenylsulfonyl-
gas evolution can be facilitated by choosing a suitable
ureas have ‘been known for a long time (cf. Example 1
cooling device. The wider the aperture of the'cooling
device is, the quicker does the ammonia escape.
lyl-) N2-methyl-, -N2-ethyl-, -N2-propyl- and -N2-butyl
of East German speci?cation No. 4,769, Example 11 of 45 The ammonia can also be removed at reduced pressure;
Danish speci?cation No. 70,259, and Example 11 of
Of great in?uence is the vigorous boiling of the ketone
Norwegian speci?cation No. 71,236).
and the vigorous stirring of the solution. It is also pos
' As a rule, compounds are used for the production of
to conduct through the reaction solution a strong
Nz-substituted sulfanilyl ureas which contain in the para
position to the sulfonyl group a group which can be con
verted into a free amino group by hydrolysis or reduc
?ow of nitrogen or of another inert gas.
tion. After completion of the formation of the sulfonyl
urea grouping, this group is then converted into an amino
It has also been suggested to subject sulfanilyl urea 55
to a so-called transamination using amines, adding acid
in order to avoid side reactions (cf. page 1, lines 91-96
and Example 4 of East German speci?cation No. 9,688).
If this suggested process is used, i.e. if sulfanilyl urea
hydrochloride‘ is heated with butylamine hydrochloride
As arylsulfonyl ureas can be used: benzenesulfonyl
urea, p-chlorobenzenesulfonyl urea, p-tosyl urea, p-me
thoxybenzenesulfonyl urea, ‘p-chloro-m-methyl-benzene-,
sulfonyl urea, m,p-dimethyl-benzene-sulfonyl urea, p-_
aminobenzesulfonyl urea, and other similarly substituted
benzenesulfonyl ureas.
As alkylamines can be used: ethylamine, n-propyl
‘amine, isopropylamine, n-butylamine, isobutylamine, sec.
butylamine, tert.butylamine, n-amylamine, isoamylamine,
sec.amylamine, n-hexylamine, 2-hexylamine, heptylamine,
in a mixture of dioxane and pyridine for a few hours, then 60 and octylamine.
The advantage of the process ‘for the production of N1-I
a reaction mixture is obtained which is only partially
sulfanilyl-Nz-alkyl ureas according to the present inven
soluble in dilute hydrochloric acid, so that not only does
is obvious: it is known that sulfonyl ureas are sensi
it contain the Nl-sulfanilyl-Nz-butyl urea formed but also
tive to acids and bases. By the liberation of the. amino
many by-products. In Example 2 of East German speci-v
?cation No. 13,762 it is suggested to react sulfanilyl urea 65 group, which in practice takes place by the sap‘oni?cation
of an acylamino group, the saponi?cation action also at
with butylamine in glacial acetic acid as solvent. The
tacks the sulfonyl urea grouping; the yield is thus reduced
repetition of this example did not give the stated yield
and, furthermore, the end product is contaminated.
of 70% but only 52% of a product which was not pure.
Contrary to the processes formerly used the ‘process
After puri?cation of the product, the yield only amounted
70 according to the present invention permits touse the free?
to 40% of the theoretical value.
p-aminophenylsulfonyl urea, and the resulting Nl-sulfan
It was now surprisingly found that N1-arylsulfonyl-N2
urea is obtained immediately in pure form.
alkyl ureas can be obtained in a very simple manner and
The following examples are given for the purpose of
illustrating the invention; they are not intended to limit
the scope'thereof.
as solvent after 3 hours of boiling and the usual working
up 148g. of Nl-p-tosyl-Nz-ethyl urea, equalling 87% of
the theoretical value, which melts at 141-142° C.
2.14 g. of p-toluenesulfonyl urea are given into a mix
ture of 800g. (=l000 cc.) of methyl isobutyl ketone and
80- g. (‘=100 cc.) of acetone, and then 80.3 g. of butyl
amine permitted‘to-?ow thereto within 15-30 minutes. A
thick but'still stirrable slurry results with a simultaneous 10
rise in temperature of 15-20° C. The stirring is con
tinued for l/z-l hour at a temperature of 20° C. The
Example 5.—N1-Sulfanilyl-Nz-n-Butyl Urea
‘ ~ whole is then heated to boiling, whereupon evolution of
NH3 takes place. The evolution of NH3 and thus the
215 g. of sulfanilyl urea are suspended in 960 g. (1200
cc.) of methyl isobutyl ketone and 87.7 g. (1.2 mol) of '
butylamine allowed to run in with stirring within the
course of 15-30 minutes. A thick but stirrable slurry re
reaction are accelerated by heating as intensively as pos- ,
sible as well as by fractioning devices. After complete
solution has'been. obtained, which occurs when the reac
I _tion"is nearly: completed and which depending on the kind ’
yof thefre?u'x heating requires from 30 minutes to 2 hours,
heatingis continued for about 10-20 minutes, followed by
When heating 150 g. of p-tosyl urea with 100 g. of n
octylamine in 700 cc. of methyl isobutyl ketone for 30
minutes to boiling and working up in a manner analogous
to that of Example 1, 176 g. of Nl-p-tosyl-Nz-n-octylurea,
corresponding to 77% of the theoretical value, which
shows a melting point of 101—102° C., are obtained.
quick cooling. * The pale yellow reaction solutionis stirred '
'well with 1000 g. of an aqueous 4% sodium hydroxide
‘solution, andjthe, aqueous solution of the sodium salt of .
sults, together with a rise in temperature of about 10° C.
In order to complete the salt formation, stirring is con
tinued for about a half hour and the reaction mixture
then heated quicklylto boiling point, whereupon evolution
of ammonia takes place. The evolution of armnonia and
thusthe reaction are accelerated by boiling as intensively
the-Nl-p-tosyl-Nz-n-butylurea then separated off. The ke~
as possible as well as by fractioning devices. After com
tone layer- is extracted twice with 50 cc. each of water. 25 plete solution has been obtained, which occurs when the
The combined aqueous solutions are adjusted to a pH
reaction is almost completed, boiling is continued for
valve of‘ 8.5-9 as quickly‘ as possible while stirring by
about 10-15 minutes and the reaction mixture is then
means-of 120 g. of 10% ‘H2804, and then ?ltered with 5 g.
poured with intensive stirring into 1000 g. of aqueous 4%
. ofv Carboraf?n-C. The carbon is washed with 150 cc. of
sodium hydroxide solution. The temperature thereby rises
water. The ?ltrate-is then allowed to run'within 1-2 hours 30 to about 40° C. After stirring well, the pale yellow so»
while stirring into a mixture of 800g. of methanol and
500,, g. of 10% H2804. Seeding is necessary after the in
troduction of 1A0 of‘ the total quantity. Cooling to 15-20°
C. is followed by adjustment to a pH value of 3-3.5 and
dium salt solution is separated off. The methyl isobutyl
ketone layer is then extracted twice with 100 cc. each of
Water. The combined aqueous solutions are adjusted to a
pHvalue of‘ 8.5 with about 90 g. of 10% acetic acid,
stirring for‘ another %-1 hour. The crystalline product
~ issubsequently?ltered off with suction or centrifuged and .
stirred with 1.0 g. of Carboraf?n-C, ?ltered and‘washed
with 700 cc. of water. The solution is diluted with a
‘washed well with water. The white product, which can
further 700 cc. of water, heated to 40-50° C., and the
"easily, be ?ltered off ‘by suction, is dried in an air drying
desired product is precipitated out, at ?rst quite slowly
loyen at‘ 401-6090. The yield is: after 3A hour're?ux
with‘ stirring and seeding, within about one hour with
:heating 243g. equally 90% of the theoretical value, with 40 about 600g; of 10% acetic acid to a pH of 6.0 to 6.5.
;a melting point, (corn) ofv 127-128° C., and after 21/2
After a few minutes, the 40-500 C. warm slurry, which
~htjmrsof re?ux heating. 230 g., equalling 85% of the theo
‘consists of voluminous small crystalline needles, is ?ltered
~ Ieticalyalue, with amelting p'oint.(corr.) of 126-127° ‘C.
off with suction: or centrifuged and washed well with
Example, '2_.-.-N1-p=Chl0r0benzenesuIfOnyLNZ-n-.
Propyl Urea
water. Drying‘ is carried out in an air drying oven at 40
45. 6.0“ C. Theyield amounts to 244 g., i.e. 90% of the
164.3 g-._ of N-p-chlorobenzenesulfonyl urea aregiven
while stirring into‘ 800 cc. of methyl isobutyl ketone.‘ Sub
sequent1y,>_45.5_lg.of n-propylamine are permitted to ?ow
in, whereby a thick-but, still, stirrable crystalline slurry re~
suits. Thewhole is‘ now heated to boilingwith continu
theoretical value.
Example 6.-—N1-Sulfanilyl-N2-n~Butyl Urea
1807 g. of sulfanilyl urea are suspended in 2000 cc. of
methyl-nrpropyl ketone, and a solution. of 329 g. of n
butylamine in 2000 cc. of methylén-propyl ketone per
ous- stirring, whereupon evolution of ammonia takes place, . mitted'to'?owinto
this suspension‘. There results a thick
lasting _35 ‘minutes.’ The now clear'solution is cooled to
but‘ still stirrable slurry. The temperature rises auto»
' 120° C. and then' stirred with 700cc. of anraqueous 4%
to 37° C. After adding a further 500 cc. of
sodium hydroxidesolution. The, aqueous, layer is sepa ' matically
methyl-n-propyl ketone, the whole is heated. to boiling
rated off and the ketone layer extracted twice with 70 cc.
while stirring, which causes a strong evolution of am~
each '’ off water. The combined aqueous solutions are
monia. After 45-50 minutes the reaction is terminated and
adjusted toa. pH valueof 8.7 by means of 10% ‘sulfuric
acid,’ stirredwith 4‘ g. of Carbora?in-C, and‘ the whole
a then ‘?ltered. The ?ltrate is given dropwise while stirring so
into a mixture of 700 cc. of methanol and ‘350 g. of 10%
sulfuric acid. The ?nal pH value is 3.2, andthe drop-1
a wise introduction lasts approximately 1% hour. The whole
is now stirred-for another 15 minutes, and the. crystalline
‘ ‘ ‘ slurry vthen ?ltered off with suction.
After washing with
‘ water and drying in an air drying ‘oven are obtained 7165 g.,
- corresponding to 85%
of the theoretical value, of N1-p.-'
chlorobenzenesulfonyl-Nz-n-propyl urea, of a melting point
of 12930.‘
everything dissolvedclearly. There follows cooling and
then stirring with 3750 cc. of aqueous 1 N NaOH. The
aqueous alkaline solution is separated-off and the ketone
layer, extractedonce morewith“ 700cc. of water. The
combined aqueous solutionsv are adjusted to a pH ‘value of
8.5, stirred with 40 g. of Carboraf?n-C and then ?ltered.
Acetic acid (2 N to 4 N- dilutions are usable) in a ?ne
jet is allowed'to ?ow. into the ?ltrate while stirring. This
is followed by adjustment to av pH value of 6-6.5 and
stirring for a. further 15-30 minutes. The crystalline
productis ?ltered off with suction, washed well with
Example 3.—N1-p-T0syl-N2-Ethyl ‘Urea
,. In a manner analogousto thatdescribed in the afore
water and dried in an air drying oven. There result 925
g. of pure N1-sulfanilyl-N2-n-butyl urea. The yield cor
responds to 91% of the theoretical value.
going examplesare ‘obtained from 150 g. of N- -to.syl
urea,’ 35 g. of ethylamine (dissolved in 200 cc. of methyl
ethylamine, n-propyl amine, isopropylamine, amylamine,
In the same manner can be reacted: patosyl urea with
isobutyl; ketone) and 1200 cc. ofemethyl isobutylk'etone 75 isoamylamine, heptylamine, octylamine. It is also possible
to use for the reaction p-methoxybenzenesulfonyl urea, p
isopropylbenzenesulfonyl urea, p - ?uorobenzenesulfonyl
urea instead of p-tosyl urea.
What we claim is:
1. In an Nl-arylsulfonyl-Nz-alkyl urea forming reaction
conducted in a solvent consisting essentially of an N
4. The method according to claim 1 wherein‘ N-aryl
sulfonyl urea is N-p-chlorobenzenesnlfonyl urea.
5. The method according to claim -1 wherein N-arylsul
fonyl urea is snlfonilyl urea.
R6. The method according to claim 1 wherein the ketone
monocyclic-arylsulfonyl urea, wherein the aryl moiety is
is methyl-n-propylketone.
a member selected from the class consisting of phenyl,
is methylisobutylketone.
lower valkylphenyl, lower alkoxyphenyl, halogenophenyl
and p~aminophenyl, and an alkylamine of from 2 to 8
carbon atoms, the improvement which comprises carry 10
ing out the reaction between said N-monocyclicarylsul
fonyl urea and alkylamine in a ratio of 1: 1.2 moles respec
7. The method according to claim 1 wherein the ketone
References Cited in the ?le of this patent
Great Britain ________ __ June 30, 1948
Switzerland ___________ __ Sept. 30, 1958
Denmark ____________ __ Nov. 28, 1949’
tively in boiling ketone having a boiling point in the
range of between 100° C. and 120° (3., and removing the
ammonia being split off as quickly as possible.
2. The method according to claim 1 wherein the ketone
Chemistry of Acetylene and Related
is substantially insoluble in water.
‘3. The method according to claim 1 wherein N-arylsul
Compounds, page '80 (1948).
rfonyl urea is p-toluenesul-fonyl urea.
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