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United States Patent O??ce 3,075,012 Patented Jan. 22, 1963 2 . 1 in excellent yields and with very good purity when per forming the reaction of an arylsulfonyl urea with an al 3,075,012 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 s-ible. PROCESS FOR THE PRODUCTION OF N1-ARYL sULFONYL-Nz-ALKYL UREAS 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 mines 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 40 than the simple transamination process. to provide the reaction kettle with a cooling device. The ' N1-p-aminophenylsulfonyl- (abbreviated=N1-sulfani 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 sible 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. 50 tion. After completion of the formation of the sulfonyl urea grouping, this group is then converted into an amino group. 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, . i. 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 tion 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 ilyl-Nz-alkyl urea is obtained immediately in pure form. alkyl ureas can be obtained in a very simple manner and 3,075,012 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. 20 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-. . 7 ' ' - 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.‘ ' r _ 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 3,075,012 5 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 6 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 FOREIGN PATENTS 604,259 332,005 70,259 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 15 ammonia being split off as quickly as possible. OTHER REFERENCES 2. The method according to claim 1 wherein the ketone Bergmann: The 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.