Patented Nov. 19, 1946 I 2,411,495 UNITED STATES PATENT. OFFICE 2,411,495 'VALUABLE DERIVATIVES OF SULPHON AMIDES AND A METHOD OF MAKING THE SAME Max Dohrn, Berlin-Charlottenburg, and Paul Diedrich, Finkenkrug, Osthavelland, Germany, asslgnors to Schering Corporation, Bloom?eld, N. J ., a corporation of New Jersey 1 > No Drawing. Application .Ianuary 31, 1939, Se rial No. 253,734. In Germany February 2, 1938 9 Claims. (Cl. 260—-397.7) 2 This invention relates to valuable derivatives of sulphonamides and a method of making the convertible thereinto, while X indicates an acyl residue of a carboxylic acid. same. In accordance with the invention by the intro As particularly valuable therapeutic agents in combating bacterial infections such duction of such an acyl residue into the sulphon- ' as amide group the hydrogen atom still present in streptococcic, staphylococcic, pneumococcic, and septicemia conditions, have proved compounds the sulphonamide group becomes replaceable by metal. By replacement of this hydrogen atom by of the type of the sulphonamides such as are described, for example, in German Pat alkali metal it is possible to convert otherwise insoluble compounds of the above mentioned class 10 of substances into compounds easily soluble in water with neutral reaction. By this means the possibility is provided of employing all the com pounds according to the invention not only as such but in the form of their water-soluble salts in 15 aqueous solution and to administer them, for example, by intravenous or subcutaneous in jection whereby a more rapid effect is promoted. In addition there is the fact that the therapeutic‘ activity of these substances is not reduced by the tents Nos. 607,537, 610,320,. 638,701, French Patents Nos. 812,053, 820,546, British Patents Nos. 482,576 and 462,765, Swiss Patents Nos. 192,699 and 192,700, U. S. Patents Nos. 2,111,768 and 2,111,913 and others; compare also the work of Fourneau, Tréfouel, Nitti and Bovet, Comptes Rendus Soc. Biol. 1936, vol. 122, pages 258-259; Tréfouel, Nitti and Bovet, Annales de l’Institut ‘ Pasteur, vol. 58, pages 30-47 (1937); Buttle, Gray and Stephenson, Lancet of 6.6.36, pages 1286 1290; Mayer, Oechslin, Comptes Rendus, vol. 205, 20 reaction speci?ed but in many ~ cases even in pages 181-182 (1937); Goissedet, Despois and Mayer, Comptes Rendus Soc. Biol. 1936, vol. 121, pages 1082-1084 and others. All these compounds creased. Even if a few of the already known compounds contain a sulphonamide group —SO2NH2 con nected to an aromatic, heterocyclic or aromatic heterocyclic residue. Very active compounds of this class of substances contain in p-position to of the sulphonamide type are capable of forming water-soluble salts as, for example, the p 25 the sulphonamide group an amino group or a group convertible thereinto. As the best known 1' aminobenzene-sulphonamide hydrochloride, the salts obtained according to the present invention are distinguished from these known salts by the fact that the latter do not pass into solution with ‘ neutral reaction and on this account can find no compounds of this type may be mentioned the p 30 application for injection purposes. sulphanilic acid amide NH2.C6H4.SO2NH2 and the For the manufacture of the compounds ac azodyestuffs derived therefrom of the type of cording to the present invention certain types 4-sulphonamido-2'.4'-diaminoazobenzene of reaction may be followed which in themselves are known to the expert. Essentially two main groups of methods of production can, be dis In compounds of this type also the nuclear bound 35 tinguished, namely; amino groups can be substituted by suitable sub 1. Such in which the residue R.SOzNH-I— is pre stituents, for example, by acyl- residues, in par viously formed and the acyl group introduced, ticular by those containing acid groups, or by 2. Such in which the residue -—NH.X is pre carboxy-alkyl residues, by carbohydrate residues, 40 viously formed and the residue R.SO2— intro by benzyl residues and the like. A whole series of duced. ' compounds of this type is di?icultly soluble or To the ?rst mentioned group of methods of insoluble in water so that the administration manufacture belongs the simplest method, namely thereof presents di?iculty. the acylation methods known per se, for instance, In accordance with the present invention par 45 by means of acid anhydrides, acyl chlorides, ticularly valuable derivatives of compounds of this ketenes and the like. If the residue R of the type are produced when in them a hydrogen atom above formula in addition contains an amino of the sulphonamide group is replaced by an acyl group, the acylation must naturally be carried 0‘: 1.; residue. The compounds thus obtained according in such a manner that together with the acylation to the iinvention correspond to the following 50 of the amino group the acylation of the sulphon formula: amide group simultaneously takes place, that is to say in general an excess of acylating agent will In this formula R indicates an aromatic, hetero be employed. 'If necessary then by partial hy cyclic or aromatic-heterocylic residue containing drolysis the acyl group of the nuclear bound at least one nuclear bound amino group or a group 55 amino group may be split off again. 2,411,495 3 4 clic nitro compound which contains a nuclear Obviously also such acylation methods can be bound basic nitrogen atom can be condensed in customary manner to the azo compound. It is also possible to reduce corresponding azoxy com pounds to the azo compounds or to dehydrogenate employed in which from the commencement only‘ an acylation of the sulphonamide group takes place and the nuclear bound amino group remains unchanged, as, for example, by causing the acyl correspondingly constituted hydrazo-compounds ating agent to react on the silver compound of to the azo compounds. the sulphonamide. The formation of the nuclear-bound amino This group of manufacturing processes includes ' group by splitting of substituents or by conver also all the processes in which such acylated sul phonamides are employed as starting materials 10 sion of another group convertible thereinto (ni tro-, azo-, halogen- and similar groups) is nec in which the nuclear bound amino group is ?rst essary in certain instances to render the com produced after the production of the acylated pound therapeutically active. Thus, such con sulphonamide group. It comprises therefore es version is necessary in the base of the p-halo sentially two stage processes in which in fact sul geno-sulfonacylamides, suchas p-chlor- or p phonamides which contain a group convertible brombenzenesulfonacetamide, since such com into the amino group are ?rst acylated whereupon pounds, as tests have shown, are inactive, and the nuclear bound amino group is produced. active compounds are produced therefrom only The various methods for converting nitrogen containing and non-nitrogen-containing groups into an amino group are Well known and are de scribed, for example, in Houben “Die Methoden der organischen Chemie,” second edition, 1923 1924, vol. 2, page 315 et seq., vol. 4, page 247 et seq., page 337 et seq., page 339, et seq., and page 354 et seq. As example may be mentioned the by conversion into the corresponding p-aminoben 20 zenesulfonacylamides. - To the second group of manufacturing proc esses belong all the processes in which such sul phonic'acids or their derivatives as contain a nuclear bound amino group or a group convert ible thereinto, primarily their halides. in partic acylation of p-nitrobenzene-sulphonamide with ular the sulphochlorides, are brought into reac converted into such an acylamino group as can employed themselves. tion in the customary manner with the corre subsequent reduction of the nitro group to the sponding acid amides in the presence or absence amino group. Instead of the nitro group also of condensing agents and/or catalysts and, if nec any other of the groups convertible into the amino group can be present, for example, the nitroso, azo, 30 essary, the nuclear bound amino group produced. Instead of the acid amides it is also possible to azoxy, hydrazo and the like groups which by employ, although less preferably, their metal ‘ reduction are converted into the amino group, compounds, for example, the silver compounds or halogen, which by treatment with ammonia, suit the like. It is also possible to cause suitable salts ably in the presence of catalysts, gives the amino of the sulphonic acids such as alkali or alkaline group; the acylamino and azo-methine groups, earth salts to react with the acid amide, in which which can be hydrolysed to the amino group, or case the operation is conducted in the presence of anacid amide or hydrazide group which can be such agents as are capable of intermediately form converted into the amino group by Ho?mann, ing from the sulphonates anhydrides or chlorides Curtius or the like degradation reactions, and others. To this group of manufacturing proc 40 which then enter into reaction with the acid amide. Such agents are, for example, sulphuryl esses belongs also the process in which the nu chloride or the chlorides of the sulphonic acids clear bound amino group before the acylation is To this group of manufacturing processes ? more easily be split off to the amino group than is the case with the acylated sulphonamide group. 45 nally belongs also the interaction of sulphinic ‘acids or their salts with acid amides which con Such groups are, for example, the carbomethoxy, tain a halogen attached to nitrogen. the carbobenzyloxy group and others as are men Of course, also other known methods for mak tioned, for example, in German Patent 556,798. ing the compounds according to this invention These can easily by reduction treatment or by as they are described, for instance, in the above hydrolysis be split off again without the acylated mentioned patents or literature references may sulphonamide group being in?uenced. Also the be employed. The essential feature of this in method of benzylating the amine group ‘can be vention consists, however, in the production of used with advantage for this type of reaction. compounds of the general formula R.SO2.NH.X. To this group of manufacturing processes be aromatic, heterocyclic or aromatic-heterocyclic amino-sulphonamide compounds are acylated in As particularly valuable starting materials for the reaction of the present invention have proved the following substances: the sulphonamide group, and then the free or p-Aminobenzene-sulphonamide, , _ long ?nally also the methods in which at ?rst again liberated nuclear bound amino group is di p-Benzylaminobenzene-sulphonamide, azotized and the diazo compound obtained cou 60 p-Aminobenzene-sulphonamido-benzene-m - sul pled in the manner known per se, corresponding, phonamide, and for example, to the directions of German Patents p-Amino - benzene - sulphonamido - p - sulphon Nos. 607,537, 610,320 and others with aromatic, amide heterocyclic or aromatic-heterocyclic bases which and their acylamino derivatives or sulphochlo are capable of coupling. There are obtained in rides, azo-dyestuffs of the type of the 4-sulphon this manner azo compounds acylated in the sul amido-'2'.4’-diamino-1.1’-azobenzene, the glu phonamide group which on the one hand contain a nuclearboun-d amino group and on the other an acylated sulphonamide group and which like wise constitute valuable therapeutic agents. Ob viously there can be employed for the manufac ture of such azo compounds also other manufac cosides of p-amino-benzene-sulphonamide and others as are described in the patents and litera ture references set forth above and in the pend ing patent applications Ser. No. 147,478 of June 10, 1937, and Ser. No. 210,746 of May 28, 1938. By interaction of the compounds according to turing methods known per se as are mentioned in the invention acylated on the sulphonamide the above speci?ed patents. Thus, for example, an aromatic, heterocyclic or aromatic~heterocy 75 group, with metal oxides, hydroxides or carbon 2,411,495 5 t6 1 di?icultly in water, linsoluble in benzene and ates or the like there are obtained the corre sponding metal'compounds; Thus it is easy to chloroform. . manufacture the alkali compounds by treating ' 'Exurru: 2 the new compounds with the calculated quantity 4-propionylaminobenzene-sulphon-propidnyl of alkali hydroxide solution or sodium carbonate 5 to a neutral reaction and, if necessary, salting out the alkali salt or precipitating it by the addition 17.2 grams of 4-aminobenzene-sulphonamide of organic solvents miscible with water. 01'. are heated to boiling for one hour with 20 cc. of — course, the salts can be isolated from their solu propionic acid anhydride. The working up, ac amide . - tions by simply evaporating the latter to dryness. 10 cording to example 1 yields the dipropionyl It is also possible, however, to produce other aminobenzene - sulphonamide. Recrystallised metal compounds, such as the alkaline earth, from alcohol it forms colorless microscopic gold, copper, mercury, silver, aluminum, magne needles of M. P. 232“ C. The product is soluble sium and the like compounds which are like in sodium carbonate solution and can be par wise of practical importance. For the manufac 15 tially saponi?ed by heating with sodium hydroxide ture of these salts there is especially suitable the solution as in Example 1, yielding 4-aminoben known method of double decomposition, accord zene-sulphon-propionyl-amide of M. P. 130 ing to which, for instance, the alkaline earth 131° C. metal salts of the acylated sulphonamides (that EXAMPLE 3 is, of alkaline earth metals whose sulphates are 20 4-acetylaminobenzene-sulphonbenzoylamide insoluble) are reacted with soluble sulphates of heavy metals. Thereby the insoluble alkaline 21.4 grams of 4-acetylaminobenzene-sulphon~ earth metal sulphate precipitates while the solu amide are dissolved with 200 cc. of N sodium ble heavy metal salt of the acylated sulphon hydroxide solution and shaken with 28.2 grams amide remains in solution and is isolated there 25 of benzoyl chloride until the benzoyl derivative from. Also organic bases as, for example, alkyla separates. The latter is ?ltered with suction and mines, alkanol amines such as ethanolamines, for puri?cation taken up in dilute sodium car bonate solution. It is ?ltered and precipitated pyridine, aniline, 1 - phenyl - 2.3 - dimethyl-4-di methylamino-S-pyrazolone, quinine and others are suitable for salt formation. Both the acylated sulphonamide/ compounds of with acetic acid. The precipitate is recrystallised '30 from dilute alcohol. The 4-acetylaminobemene sulphonbenzoyl-amide forms needles which on the formula R.SOz.NH.X and also their metal and heating decompose at 245-246° C. By heating other derivatives are intended to find application with sodium hydroxide solution, as in Example 1, not only as therapeutic agents but also as inter partial saponi?cation takes place. The 4-amino mediate products for the manufacture of other 35 benzene-sulphonbenzoyl-amide obtained has the _ pharmaceutical and. technically valuable sub stances, for example, for the manufacture of plant protecting agents and the like. The following examples illustrate the invention without, however, limiting the same to them: melting point of 179-186" C. EXAMPLE 4 40 26.2 grams of 4-benzylaminobenzene-sulphon EXAMPLE 1 4-aminobeneene-sulphonacetyl-amide 17.2 grams of 4-aminobenzene-sulphonami‘de amide are heated for some hours with 250 cc. of acetic anhydride. The working up according to Example 1 yields the 4-benzylaminobenzene sulphonacetylamide. It is puri?ed by recrystal are heated to boiling with 75 cc. of acetic anhy dride for one hour and thereupon the diacetyl lisation from alcohol and then forms microscopic needles of melting point of 143-144“ C. product caused to separate by stirring into ice water. After recrystallisation from alcohol the 4 EXAMPLE 5 acetylaminobenzene-sulphonacetyl - amide forms colorless prisms of melting point 253° C. with decomposition. The product is easily soluble in alkalies and forms neutral salts. The acetylation can also take place with acetyl chloride. Instead of the 4-aminobenzene-sulphonamide also 4 acetylaminobenzene-sulphonamide can be em 4-benzylaminobenzene-sulphonacetamide 50 4.4’- acetylaminobenzene-sulphonamidobenzene sulphonacetylamide 32.7 grams of 4.4’-aminobenzene-sulphon amidobenzene-sulphonamide are heated to boil-v ing with 200 cc. of acetic anhydride. ~ After solu tion has taken place the whole is boiled for a further hour and then the diacetyl compound caused to separate by pouring the solution into ice water. -The precipitate is puri?ed by dissolv same product. ing in sodium carbonate solution and precipita By heating the diacetyl compound with so dium hydroxide solution partial saponi?cation 60 tion of the ?ltrate with acetic acid. Recrystal lised from dilute alcohol the product forms color of the acetyl groups takes place. 25.6 grams of less needles which melt at 178° C. By partial diacetyl compound are heated to boiling for some saponi?cation with normal sodium hydroxide hours with 100 cc. of 2 N sodium hydroxide solu solution the corresponding amino product of tion. The precipitate produced by acidi?cation ployed. The action of 4-acetylaminobenzene sulphonic acid chloride on acetamide yields the of the solution with acetic acid is ?ltered off and 65 M. P. 187° C. is obtained. treated with dilute sodium carbonate solution. EXAMPLE 6 The 4-aminobenzene-sulphonacetylamide passes 4-acetylaminobenzene-sulphonamido-3' into solution while the simultaneously formed 4 benzene-sulph0nacet11lamide acetylaminobenzene=sulphonamide remains un dissolved. It is ?ltered with suction and the ?l 70 32.7 grams of 4-aminobenzene-sulphonamido B-benzene-sulphonamide of M. P. 156° C. (pro- trate again acidi?ed with acetic acid. The 4 aminobenzene-sulphonacetamide separates out duced by the action of 4-acetylaminobenzene and is recrystallised from water. It forms color sulphonic acid chloride on 3-aminobenzene-sul phonamide and subsequent saponi?cation of the less lustrous rhombic crystals of M. P. 181° C. It is easily soluble in alcohol and acetone, more 75 acetyl group of the condensation product) are 2,411,495 . - 7 and then introduced into ice water. The precipi tated carbethoxy-sulphanilic acid chloride is for puri?cation dissolved in cold methyl alcohol~ and heated with 200 cc. of acetic anhydride for one hour to boiling and thereupon the diacetyl product isolated as described in ‘Example 5. After recrys tallisation from dilute alcohol the product melts precipitated again by the addition of water. The at 145-146°. By partial saponi?cation the corre sponding amino compound is obtained. melting point is 104-105“ C. By introduction of EXAMPLE 7 4-acetylsulphonamidobenzene-2'.4'-diamino-1.1' - azobenzene ammonia into the ethereal solution of the car bethoxy-sulphanilic acid chloride there is pro duced in good yield the 4-carbethoxy-sulphanilic acid amide of melting point of 238° C. 10 244 grams of 4-carbethoxy-aminobenzene-sul phonamde, 1.25 litres of glacial acetic acid and 21.4 grams of 4-aminobenzene-sulphonacet 80 grams of acetyl chloride are heated to boil amide are diazotised in hydrochloric acid solution with 6.9 grams of sodium nitrite and the cold - ing for 2 hours. The acetylatedv product is intro duced into water, ?ltered with suction and repre diazonium chloride solution treated with a hydro chloric acid solution of 11 grams of m-phenylene 15 cipitated. It melts .after recrystallization irom dilute acetone at 244° C. . diamine. The coupling product immediately For splitting o?.’ the carbethoxy group the separates as a dark red precipitate. It is ?ltered 4 - carbethoxy amino - benzene - sulphonacetyl with suction, taken up with dilute sodium car amide is dissolved in seven times the quantity oil bonate solution, ?ltered and acidi?ed in the hot with acetic acid. The dyestu? separates in the 20 2 N sodium hydroxide solution and the solution heated for 10 minutes to 80° C. By acidi?cation form of blue-red leaflets of‘ metallic lustre. On with acetic acid the 4-aminobenzene-sulphon heating decomposition takes place at 180° C. acetylamide is precipitated and is puri?ed by The same product is obtained when the » 4 recrystallisation from water. Melting point 181° sulphonamido - 2'.4'- diamino-l.1’-azobenzene is acetylated and partially saponi?ed. The dyestu? 25 C. The yields according to this process corre spond to those given imijxample 8. Instead of 4-carbethoxy-aminobenzene-sul is easily soluble in dilute sodium, carbonate solu tion. , phonamide there can also be employed as start Exmrta 8 4-aminobenzene-sulphonacetylamide ing material the carbomethoxy compound; it is 30 obtained in the following manner: 82.3 grams of the sodium salt or carbometh 172 grams oi’ sulphanilic acid amide are dis solved in 2000 cc. of N sodium hydroxide solution oxy-sulphanilic acid (Niilting, Berichte 21, 3155) 4-N-carbonic acid benzyl ester. aminobenzene tion and washed _i’ree from acid. The amide is are ground with 70 grams oi! phosphorus penta and to the solution at 0°.C. with stirring and chloride. The solid mass is introduced into ice cooling 340 grams of benzyl-chlbrocarbonic acid ester added. After several hours the precipitated 35 water, the undissolved portions ?ltered with suc sulphonamide is separated, washed with dilute hydrochloric acid and water and recrystallised from methyl alcohol. Melting point 192-192.5° 40 ‘C. The yield amounts to 250 grams. By one hour's boiling of this product with ?ve . times the quantity of acetic anhydride and pour 21.4 grams of 4-aminobenzene-sulphonacet amide are heated to boiling with 17.1 grams of glucose and 200 cos. of absolute ethyl alcohol ' until a clear solution is produced. From the solution on long standing the glucose compound ciystallises in colorless needles. The crystals are separated and recrystallised from absolute ethyl The --4-N-carbonic acid benzylr ester aminoben zene-sulphonacetylamide melts after recrystal ' lisation'from methyl alcohol at 167-168° C. The yield amounts to 200 grams. r ilic acid amide melts at 226-227" C. EXAMPLE 10 4-aminobenzene-sulphonacetamide-glucoside ing or the solution into water the-acetyl derivative is precipitated. It is ?ltered with suction, taken up in dilute sodium‘ carbonate solution. ?ltered from any unchanged starting material and in the ?ltrate precipitated again by hydrochloric acid.‘ obtained by introduction of ammonia'into the ethereal solution of the sulphochloride (melting point 117-118“ C.) The carbomethoxy-sulphan alcohol. The melting point is 191° C. The com . pound is easily soluble in water, more dimcultly in ethyl alcohol. The alkali salts are easily solu ble in water with neutral reaction. To split off the carbobenzyloxy group, 200 grams of the 4-N-carbonic acid benzyl ester ami nobenzene-sulphonacetylamide are dissolved in 3 litres of alcohol and with the addition oi.’ 5 I grams of'palladium black shaken with hydrogen EXAMPLE 11 4.4’-disulphonacetamide-diphenyl-urea so long as the latter is still taken up. 'For this purpose 7.6 litres of hydrogen are employed. Into a solution of 21.4 grams of 4-amino-ben The solution is ?ltered oil from catalyst, concenzene-sulphonacetamide in 200 cc. of 2 N sodium trated and the residue recrystallised from water. 60 hydroxide solution is introduced at 50° C. a strong The yield amounts to 106 grams of 4-amino stream of phosgene. When the reaction is com benzene-sulphonacetylamide of melting point of plete the precipitate produced is ?ltered with 181° C. The same _ld is obtained when the suction and for puri?cation precipitated from an catalytic hydrogenat'on is carried out in aque alkaline solution in the hot with acetic acid. The 65 product forms colorless microscopic needles ous alkaline instead of in alcoholic solution. The splitting off of the benzyl-carbonic acid residue can also “take place by several hours treatment with three times the molar quantity of normal sodium hydroxide solution. at 60° C. which decompose at 255° C. The yield is quanti tative. The product is very di?lcultly soluble in organic solvents. The water-solubility of its alkali salts is considerable. 70 , ' Exmrnn 9 40 grams oi.’ carbanilic acid ethyl ester (Hente schel, Berichte vol. 18, page 978) are,‘ introduced '1 - ' - EXAMPLE 12 .4i-aminobenzene-sulphon-nicotoylamide 24.4 grams of 4-carbethoxy-sulphanilic acid at 0° C. into 160 grams of chlorsulphonic acid. The mixture is heated for an. hour to 55-60° C. 76 amide are dissolved in 250 cc. 0! pyridine and 2,411,495 with stirring and cooling 14.2 grams of nicotinic acid chloride introduced drop by drop. The clear solution is introduced into ice water and treated with hydrochloric acid to an acid reaction to Congo red. The precipitate is isolated and re crystallised irom dilute alcohol. 10 and the ?ltrate is precipitated with hydrochloric acid. The precipitate consists of 4-benzylamino benzene-sulphonacetamide which 'on recrystalli sation from alcohol melts at 143-144° C. The yield amounts to 15 grams. EXAMPLE 17 4-acetylsulphamidophenyl-azo-I ’ (naphthal The product forms needles of M. P. 241° C. For saponi?cation of the carbethoxy‘ group 30 6'.8'-disulphonic acid) grams of 4-carbethoxyaminobenzene-sulphon nicotoylamide are allowed to stand for 24 hours 10 21.4 grams of 4-aminobenzene-su1phon-acetyl- ' in 210 cc. of 2 N sodium hydroxide solution. The amide obtained, for instance, according to Ex solution is then acidi?ed with acetic acid, the ample 1 are diazotized and in sodium carbonate precipitate ?ltered with suction washed with solution coupled with a solution of 35 grams of water and recrystallised from dilute alcohol. 2-naphthol-6.8-disulphonic acid sodium salt. In The 4 - aminobenzene - sulphon - nicotoylamide order to isolate the reaction product ‘the solution forms colorless needles and melts at 246° C. ' is slightly acidi?ed and the dyestuff is salted out by addition of sodium chloride. The disodi EXAMPLE 13 um salt obtained thereby is recrystallised from 4-aminobenzene-salphonbatyryl-amide dilute alcohol and forms vermillion-reddish col_ 24.5 grams of 4-carbethoxysulphanilic acid 20 ored prismatic needles which decompose on heat amide and 150 cc. of butyric acid anhydride are ing at 333°C. stirred into water after heating for 1 hour. EXAMPLE 18 Thereby the acylated product precipitates in the 4-aminobenzene-sulphonpropionyl-amidé form of an oil. By recrystallisation of the solidi 24.5 grams of 4-carbethoxy-aminobenzene ?ed oil from dilute alcohol the 4-carbethoXy 25 sulphon-amide are heated with 150 cc. of pro aminobenzene-sulphon-butyryl-amide is ob pionic acid anhydride for one hour to boiling. tained in the form of needles of melting point On stirring the mass into ice-water an oil pre 217-218". cipitates that soon solidi?es. After recrystallisa The saponi?cation is carried out as described above by treatment with 2 N sodium hydroxide 30 tion the 4-carbethoxy-aminobenzene-sulphon propionyl-amide is obtained in the form of solution. The 4-aminobenzene-sulphonbutyryl needles having a melting point of 208° IC. The amide obtained thereby yields on recrystallisa yield amounts to 24 grams. tion from alcohol a product having a melting The saponi?cation of the carbethoxy residue point of 125°. EXAMPLE 14 4-aminobenzene-sulphoncrotonyl-amide 24.5 grams of .4-carbethoXy-sulphanilio acid 35 is carried out in the same manner as described in Example 9, i. e. by heating with 2 N sodium hydroxide solution. The 4-aminobenzene-sul~ phonpropionyl-amide obtained ‘therefrom by amide are heated for 2 hours to 145° C. with acidifying with acetic acid solidi?es after a short 125 grams of crotonic acid and 11 grams of 40 time and forms crystals that on recrystallisation crotonic acid chloride. After cooling the reac from dilute alcohol melt at 130-131“ C. tion mixture is stirred into 2 liters of water. EXAMPLE 19 The undissolved portion is separated, taken up in sodium carbonate solution and precipitated 4-aminobenzene-sulphon-phenacetyl-amide after ?ltration with acetic acid. The crotonylic 24.4 grams of 4-carbethoXy-sulphanilic acid derivative redissolved from alcohol melts at 224° C. amide are heated with 16 grams of phenacetyl chloride for several hours to 160-170° C._ The Saponi?cation yields the 4-aminobenzene cooled reaction mixture is dissolved in dilute sodium carbonate solution and is acidi?ed after sulphoncrotonyl-amide which on recrystallisa tion from water melts at 175° C. EXAMPLE 15 ?ltration, with hydrochloric acid. The 4-car bethoxy-sulphanilic acid phenacetyl amide pref cipitated thereby is recrystallised from alcohol 4-acetylaminobenzene-suZphon-pmitmbenzoyl and melts at 209° C. The saponi?cation of this compound is carried out by treating the same with 2 N sodium hy droXide solution. The 4-aminobenzene-sulphon amide 21.4 grams of 4-acetylaminobenzene-sulphon ‘ amide are dissolved in 200 cc. N sodium hy droxide solution and are shaken with 18.6 grams of 4-nitrobenzoy1 chloride for several hours. The phenacetyl-amide obtained thereby melts after ?ltered solution is‘ acidi?ed, the precipitate is dissolved in sodium carbonate solution, again 60 ?ltered, and the ?ltrate precipitated by means of acid. On recrystallisation from alcohol the 4-acetylaminobenzene-sulphon-p - nitrobenzoyl amide of M. P. 256° C. is obtained. EXAMPLE 16 4-benzyZaminobenzene-sulphon-acetyl-amide - 21.4 grams of 4-aminobenzene-sulphon-acet ylamide obtained, for instance, according to EX ample 1 and having a melting point of 181° C. are heated with 12.6 grams of benzylchloride, 24 grams of calcium carbonate, and 500 cc. of water for several hours while stirring, to boiling. After adding 6 grams of sodium carbonate the mix ture is again heated to boiling, ?ltered while hot, recrystallisation'from dilute alcohol at 182° C. EXAMPLE 2O 4-carbethomy-aminobenzene-sulphonamino acetic acid amide 24.4 grams ‘of 4-carbethoxy-sulphanilic acid amide and 50 grams of chloro acetic acid anhy dride are heated for one hour to 120-125° C. The reaction mixture is then triturated with water, the undissolved is removed by ?ltration, and is recrystallised from dilute alcohol. It melts at 229° C. The 4-carbethoxy-aminobenzene-sul phon-chloro-acetic acid amide yields on treat ment with concentrated ammonia solution at ordinary room temperature 4-carbethoxy-amino benzene-sulphonamino-acetic acid amide which 75 on_ recrystallisation from water melts at 223° C. 2,411,495 , 11 1-2 - Exmem 21 chloride and the mixture is heated for one hour to ‘190° C. The pulverised reaction mixture is dissolved in dilute sodium carbonate solution, ?ltered, the ?ltrate acidi?ed by means of hydro , 4-,‘aminobenzene-sulphonsalicyltc acid amide 24.4 grams ' of 4-carbethoxy-sulphanilic acid amide and 15.7 grams of salicylic acid chloride chloric acid, the precipitate ?ltered off by suction, and recrystallised from dilute alcohol. The di carbethoxy compound melts at 201° C. By treat are heated for several hours to 170-180° C. The reaction mixture is then dissolved in dilute sodium carbonate solution. The solution is ?ltered and ing the same with 2 N sodium hydroxide solution precipitated with hydrochloric acid. By recrys the two carbethoxy groups are split off and the tallisation from glacial acetic acid the reaction 10 4.4’-diamino-diphenyl-disulphon-mucic acid di product is obtained in a pure state and melting at amide having a melting point of 233° C. is ob 242° C. The saponi?cation with 2 N sodium hy tained. droxide solution yields 4-aminobenzene-sulphon salicylic acid amide which on recrystallisation from water melts at 200-201° C. 15 EXAMPLE 22 24.4 grams of 4-carbethoxy-sulphanilic acid I 4-aminobenzene-sulphonfuroyl amide 48.8 grams of 4-carbethoxy-sulphanilic acid amide are dissolved in 250 cc. of pyridine and -mixed while cooling and stirring, slowly and gradually with 26.5 grams of pyromucic acid chlo ride. After standing for some time the solution is poured into ice-water, ?ltered and the con densation product precipitated by acidifying with amide are dissolved in 250 cc. of pyridine. 4-aminobenzene-sulphonfuroyl-amide is obtained on acidi?cation. It forms a crystalline mass that To this solution there are added drop by drop while stirring 11 grams of chloro carbonic acid ethyl 20 ester. The solution is. heated for several hours to 60-'70° C., then diluted with 5 times its amount of water and acidi?ed with hydrochloric acid. The precipitate obtained is dissolved in dilute so dium carbonate solution in order to remove any 25 non-reacted starting material, the solution is ?l hydrochloric acid. The product purified by re precipitation, melts at 259° C., with decomposi tion. The yield is almost quantitative. By treat ing this product with 2 N sodium hydroxide solu tion the carbethoxy group is split off and the 30 ' ExAmPLz 26 4-aminobenzene-sulphoncarbethowy-amide tered, and the 4-carbethoxy-aminobenzene-sul phon-carbethoxy-amide is precipitated from the ?ltrate by means of hydrochloric acid. On re crystallisation from alcohol needles having a melting point of 162° C. are obtained. ' By treating this product with 2 N sodium hy droxide solution the carbethoxy group is split 01! on recrystallisation from water melts at 188 from the nuclear amido group. The 4-aminoben 189° c. ' zene-sulphoncarbethoxy-amide obtained thereby ExAmLn 23 4-aminobenzene-sulphon-hydnochaulic-acid 35 melts after recrystallisation from alcohol at 133° C. It forms alkali salts that are readily soluble in water with neutral reaction. » ~ amide Instead of reacting 4-carbethoxy-sulphanllic 24.4 grams of 4-carbethoxy-sulphanilic acid acid amide with- one mol chloro carbonic acid amide are slowly heated with ‘29.6 grams of hydno 40 ester one may proceed in such a manner that one chaulic (chaulmoogric) acid chloride (Wagner mol of sulphanilic acid amide is reacted with 2 Jauregg und Voigt, Berichte der Deutschen Chem mols of chloro carbonic acid ester, thereby yield ischen Gesellschaft, vol. 71, page 1975) to 148° C. ing the same dicarbethoxy-sulphanilic acid The reaction product is poured into water and is brought into solution with an amount of sodium EXAMPLE 27 carbonate su?icient to dissolve the product. After 4-carbethoxy-aminobenzene-sulphon-carb ?ltration hydrochloric acid is added and the pre ethomlamide cipitate is recrystallised from dilute alcohol in the presence of charcoal. The product forms 26.4 grams of 4-carbethoxy-sulphanilic' acid colorless globular crystals having a melting point 50 chloride are heated with 100 grams of urethane ‘of 131° C. ' to 140-150° C. until a sample is readily and com EXAMPLE .24 pletely soluble in dilute sodium carbonate solu tion. The reaction mixture is then dissolved in 4.4’-diaminodiphenyl-disulphonadipic acid very dilute sodium carbonate solution, ?ltered. diamide and the, ?ltrate acidi?ed with acetic acid. The 48.8 grams of 4-carbethoxy-sulphanilic acid precipitate is recrystallised from alcohol and cor amide are heated with 18.3 grams of adipic acid responds with the product obtained according to dichloride for several hours to 150° C. The solid the preceding example. mass is broken into pieces and is dissolved with EXAMPLE 28 I sodium carbonate solution. After acidifying the amide. ?ltered solution, the precipitate is recrystallised from a large quantity of dilute alcohol. The product melts at 229° C. with decomposition. The splitting off of the carbethoxy group is carried out in customary manner by means of 2 N sodium hydroxide solution. Thereby the 4.4'-diamino diphenyl-disulphon-adipic acid diamide is ob tained that after decrystallisation from dilute alcohol melts at 212° C. EXAMPLE 25 ‘ I Salts of 4-aminobenzene-sulphon-acetamide (a) Sodium salt: 21.4 grams of 4-aminoben zene-sulphon-acetamideare dissolved in 100 cc. of N sodium hydroxide solution and the sodium salt is precipitated with alcohol after concentrat ing the solution. On recrystallisation from dilute alcohol the salt melts at 257° C. (b) Barium salt: 21.4 grams of 4-aminoben zene-sulphon-acetamide are dissolved in an aque _ 4.4’-diamin0-diphenyl-disulphon-mucic acid diamide 48.8 grams of 4-carbethoxy-sulphaniiie acid amide are mixed with 24.7 grams of music acid ous solution of 15.8 grams of barium hydroxide, the solution is evaporated to dryness and the‘resi due is recrystallised from dilute alcohol. Melt ing point: 185° C. (with decomposition). (c) Copper salt: The aqueous solution of 5 grams of the barium salt of 4-aminobenzene-sul 2,411,495 - 13 14 - phon-acetamide is mixed with 2.2 grams of copper sulphate. The ?ltrated solution is evaporated to dryness. A greenish powder is obtained. Exams 31 4-aminobenzene-sulphonnicotouliamide ‘ sodium salt (d) Ammonium salt: 4-ami‘nobenzene-rsul phon-acetamide is dissolved in aqueous ammonia solution to neutral reaction and evaporated to dryness, A crystalline powder is obtained which on recrystallisation from alcohol melts at 156° C. with decomposition. (e) Pyridine salt: 4-aminobenzene-sulphon acetamide is dissolved while heating in pyridine. The pyridine salt precipitated on cooling is re crystallised from alcohol. It has a melting point - 27.7 grams of‘ 4-aminobenzene-sulphon-nico toyl-amide are dissolved in 100 cc. of N sodium hydroxide solution. The solution is evaporated to dryness. The residue is recrystallised from di lute alcohol and gives a product that on heating decomposes beginning at 270° C. whereby color ation takes place. ' Exlunmr: s2 4-aminobenzene-salphon-acetamide-alu ' of 120° C. (f) Diethanol amine salt: 21.4 grams of 4-ami 15 nobenzene-sulphon-acetamide are brought into solution by means of 10.5 grams of diethanol amine in 100 cc. of water. The residue obtained on evaporating the solution to dryness is recrys - coside-magnesium salt 37.6 grams of 4-aminobenzene-sulphon-acet amide glucoside are dissolved in 150 cc. of water and boiled with 4.2 grams of magnesium carbon ate. After evaporated to dryness the filtered so tallised from dilute alcohol. Melting point of the 20 lution, the residue is recrystallised from dilute alcohol and yields a'salt melting at about 165 salt: 155° C. (not sharp). 167" C. ' 0 (9) Calcium salt: 21.4 grams of 4-aminoben Examine 33 zene-sulphon-acetamide are dissolved in 100 cc. of water while heating. To this solution there 4.4'- aminobenzene - sulphon - amidobenzene are added 5.0 g. of calcium carbonate. After 25 sulphon-acetamide sodium salt boiling for a short time it is ?ltered and the ill 36.9 grams of 4.4'-aminobenzene-sulphon trate evaporated to dryness. Thevresidue is re amidobenzene-sulphon-acetamide are dissolved crystallised from dilute alcohol. in 100 cc. of water and 100 cc. of N- sodium hy (h) Silver salt: The aqueous solution 'of_ 4-ami nobenzene-sulphon-acetamide sodium is mixed 30 droxide solution. From the concentrated solu tion alcohol precipitates the sodium salt in crys . with a silver nitrate solution. The silver salt pre cipitates, is ?ltered off by suction, and is washed with water, alcohol, and ether. The product has a melting point of 216° C. ~ talline form. - ' 1 EXAMPLE 34 4-benzylammobenzene-sulphon-acetamide calcium salt (i) Mercury salt: From an aqueous solution of 35 the sodium salt of 4-aminobenzene-sulphon-acet 30.4 grams _ of 4-benzylaminobenzene-sulphon amide the mercury salt of this sulphon amide acetamide are heated with 200cc. of water and compound is obtained by precipitation by means 5 grams of calcium carbonate for several hours to of a mercury acetate solution. It has a melting boiling. . point of 251° C. (under decomposition). 40 The ?ltrate is concentrated by evaporation and (k) Quinine salt: 31.4 grams of 4-aminoben the syrupy residue is triturated with absolute zene-sulphon-acetamide and 32.4 grams of qui alcohol whereby the calcium salt separates in nine are dissolved in 200 cc. of alcohol. After crystalline form having a melting point of 268° distilling off the alcohol the quinine salt remains. C. (thereby decomposing). _ It is soluble in water and melts at about 73° C. "7". Examine 35' (l) Morphine salt: 21.4 grams of 4-aminoben zene-sulphon-acetamide and 30.3 grams of mor 4-acety'l-sulphamido-2'.4'-dia1nido-1 .1 ' -azo phine are dissolved while heating in 200 cc. of al benzene-sodium salt cohol. The salt is precipitated by adding ether 33.3 grams of 4-acetyl-sulphamido-2'.4'-dia and has a melting point of 160° C. (not sharp). EXAMPLE 29 4-aminobenzene-sulphonpropionul-amide calcium salt 22.8 grams of 4-aminobenzene-sulphonpropi onyl amide are dissolved while heating in 150 cc. of water. To this solution 5.0 grams of calcium carbonate are added. After heating to boiling the solution is ?ltered and the ?ltrate is evapo rated to dryness. The residue is recrystallised from dilute alcohol and has a melting point of 283° C. (with decomposition). mldo-1.1’-azobenzene are dissolved in 200 cc. of water and 100 cc. of N sodium hydroxide solu tion while heating. On addition of alcohol and ether the sodium salt crystallises from the solu tion in orange-brown needles of melting point of 55 207° C. (thereby decomposing). EXAMPLE 36 } 2-aminopyridine-5-sulfonacetamide 10 grams of 2-aminopyridine-5-sulfonamide 60 obtained from 2-chloropyridine-5-sulfonamide by reaction with concentrated aqueous ammonia solution at 150° C. in a closed container under pressure, are heated with 100 cc. of acetic acid anhydride for 1 hour to boiling; after cooling the 65 solution is poured into about 1 liter of water while 4-aminobenzene-sulphonfuroyl-amide mag nesium salt stirring, the precipitate obtained ?ltered of! by suction and recrystallized from water while add ing animal charcoal. The 2-acetyl-aminopyri dine-5-sulfonacetamide (melting point 278-79° 26.6 grams of 4-aminobenzene-sulphonfuroyl 70 C.) is soluble in sodium carbonate solution and amide are dissolved while heating in 200 cc. of insoluble in acids. It can be transformed by par water. The solution is heated to boiling with 4.2 tial saponi?cation into the 2-aminopyridine-5 grams of magnesium carbonate. The ?ltered so-. sulfonacetamide. lution is concentrated by evaporation and is re In‘ the same manner there is obtained on acet crystallised from dilute alcohol. 75 ylatlon of 2-anilidopyridine-5-sulionamide or 2,411,405 , 15 8. N'-acylsulfanilamidesbof the following for melting point 178° 0., produced from z-chloro pyridine-5-sulfonamide by boiling with aniline, the 2-anilldo-pyridine-5-sulfonacetamide. Exaurm 3'7 mula: » . Cl 4. 4-amino-benzene-sulfanacetylamide. 4-acetylsuljamidobenzene-Lihaze-226’ ' . 5. The sodium salt of 4-amino-benzene-sul diaminomlridine fonacetylamide. . 6. In a process for the manufacture of Nl-acyl 5 grams of 4-aminobenzene sulfonacetamide 10 sulphonamides, the step comprising subjecting a are diazotized in a customary manner in hydro sulphonamide compound having directly attached chloric acid solution with 1.6 grams of sodium to the sulphur atom a ring carbon of an aromatic' nitrite. To the diazo solution there is added a residue which has an amino group linked through hydrochloric acid solution of 2.6 grams of 2.6-di the nitrogen to a ring carbon in p-position to the aminopyrid'ine. After adding sodium acetate to this solution a voluminous, orange-reddish pre— 15 first-mentioned carbon, to the action of at least 2 mols of an acylating agent to acylate both the cipitate of the reaction product is formed which amidic nitrogen and the nuclearly bound amino group, the sulfonamide group being converted is ?ltered off by suction, washed with water and recrystallized from alcohol. The azo compound forms orange-reddish needles of melting point, 191-192? C. and is soluble in sodium carbonate solution. Instead of pyridine compounds other hetero cyclic compounds may be used likewise such as into the group -—SO2.NH.OC.R, the group —OC.R being the acyl radical of a carboxylic acid. ' 7. In a process for the manufacture of NL-acyl sulphonamides, the steps comprising subjecting a sulphonamide compound having directly at tached to the sulphur atom a ring carbon of an ‘ those of the quinoline, pyrrol, indol, pyrazol and 25 aromatic residue which has an amino group the like series. linked through the nitrogen to a ring carbon in p-position to the ?rst-mentioned carbon, to the action of at least 2 mols of an acylating agent to ployed, for example, the anhydrides or halides of acylate both the amidic nitrogen and the nu higher fatty acids such as those of palmitic acid, hydnocarpus acid, phenyl-cinchoninic acid, Pyri 30 clearly bound amino group, the sulfonamide group being converted into the group dine carboxylic acids and others. It is true that sulphonamides amino substituted in the nucleus have previously been acylated, compare French'speci?cation 820,546. As, how the group —0'C.R. being the acyl radical of a ever, is shown by the more detailed description 35 carboxylic acid, and partially hydrolyzing the acylated product to regenerate only the nuclear of the speci?cation in this case always 1 mol of amino group. acylating agent is employed for 1 mol of the sul 8. Process for the manufacture of 4-amino phonamide. By this means, however, only the benzenesulphonacylamides, comprising subject nuclear bound amino .group is acylated. Accord ing p-aminobenzenesulpho'namide to the action ing to the process of the present application, of at least 2 mols of an acylating agent to‘ acylate however, an excess of acylating agent is employed both the amidic nitrogen and the nuclearly bound so that both the nuclear bound amino group and amino group, the sulphonamide group being con also the sulphonamide group are acylated; one verted into the group —SO2.NH.OC.R, the group of these acyl groups and in fact that which has --OC.R being the acyl radical of a carboxylic entered the nuclear bound amino group can then acid, and saponifying the 4-acylamino group to . .5 4 again easily be split off so that the free amino Instead of the acylating agents employed in these examples obviously also others can be em group is reformed. yield the 4-aminobenzenesulphonacylamide. ' . 9. In a process for the manufacture of Nl-acyl In the subjoined claims the term "aromatic” is to be understood as embracing compounds hav sulphonamides, the steps comprising subjecting ing either a phenyl or a pyridyl radical, e. g. the 50 a sulphonamide compound having directly at tached to the sulphur atom a ring carbon of an aromatic residue which has an amino group linked through the nitrogen to a ring'carbon in What we claim is: p-position to the ?rst-mentioned carbon, to the 1. A 4-aminobenzene-sulfonacetylamide of the 55 action of at least 2 mols of an acylating agent general formula to acylate both the amidic nitrogen and the nuclearly bound amino‘ group, the sulfonamide benzene, pyridine and quinoline compounds dis closed hereinabove. > group being converted into the group wherein Y is a member of the group consisting ‘of hydrogen and metals. 2. A process for preparing N'-acylsulfanil amides which comprises reacting sulfanilamide 60 the group —-OC.R being the acyl radical of a car boxylic acid, and converting the Nl-acyl sul with at least two equivalents or a member of ' ' yphonamide’s into salts by treatment with a mem thegroup consisting of monoliasic aliphatic car boxylic acid halides arid anhydrides, and hy drolysing the N4-acylamino group only of the resulting product. her" of the group consisting of organic and in 65 ’o'ig'anic bases. - ' . MAX DOHRN. PAUL DIEDRICH.