UNITED STATES PATENT OFFICE 2,429,20 P-AMINOBENZENE-Sulfonamides and THER MANUFACTURE Henry Martin and Rudolf Hirt, Basel, Switzer Land, Assignors to J

Patented Oct. 21, 1947 2429,207

UNITED STATES PATENT OFFICE 2,429,20 p-AMINOBENZENE-SULFONAMIDEs AND THER MANUFACTURE Henry Martin and Rudolf Hirt, Basel, Switzer land, assignors to J. R. Geigy A. G., Basel, Switzerland No Drawing. Application September 1, 1942, Se rial No. 456,942. In Switzerland June 21, 1940 3 Claims. (C. 260-397.) 2 It has been found that valuable p-aminobenz Or condensing action may be used at the same ene Sulfonic acylamides of the general formula, time. The invention is illustrated but not limited by the following examples. The parts are by 6 weight, unless otherwise stated. are obtained, in which R, indicates an unsatu Eacample 1 rated, branched, aliphatic radical, when sulfon 21.4 parts of p-acetylamino-benzene sulfon amides of the benzene series, which in the p amide and 18.2 parts of dimethylacrylic acid an position to the sulfonamide group contain a 0 hydride (produced from dry sodium dimethyl nitrogen-containing group, are re-acted With un acrylate and dimethyl acrylic acid chloride; boil Saturated, branched, aliphatic carboxylic acids ing point 18 140-145 C.) are heated together or their functional derivatives and the p-posi in a flask in the oil bath to 200-210° C. There tion nitrogen group is converted, if necessary, is thus formed slowly a homogeneous fused mass. into an amino group. Compounds of this type 15 After heating for one hour it is dissolved in a have not become knoWn up to the present time; hot diluted sodium carbonate solution, treated they are distinguished from other p-amino With Some animal charcoal and filtered. The benzene sulfonamides by their superior activity condensation product is precipitated from the relatively to infection promotors and by their filtrate by acidification with hydrochloric acid, slight poisonousness. 20 drawn off and re-crytallised from alcohol. Melt As Sulfonamides of the benzene series which ing point 231 C. in the p-position to the Sulfonamide group con By Saponifying the acetyl amino group with di tain a nitrogen-containing group, may be men lute Soda, lye on the Water bath, p-aminobenzene tioned: p-aminobenzene Sulfonamide, p-acyl sulfone-6,6-dimethyl acrylic acid amide with aminobenzene sulfonamides, p-nitrobenzene sul 25 fonamides and so forth. The nitro group may melting point 177-178° C. is obtained. be replaced by any other group, capable of being Eacample 2 converted by reduction into the amino group, for 21.4 parts of p-acetyl aminobenzene sulfon example the nitroso, a Zo, a ZOXy or hydrazo group. amide, 10 parts of dimethyl acrylic acid and Azomethine- and acyl-amino groups can be 30 20 parts of phosphorus pentoxide are treated with converted into amino groups by hydrolysis. It 150 parts by volume of chlorobenzene and refluxed is advantageous to select from the acyl radicals for 4 hours. Then some water is added thereto those which are easily capable of being split off and the chlorobenzene is distilled off with steam. again. Such radicals are for example the acetyl The residue is then poured into a sodium car Or the carbonnethoxy radicals, which are easily 35 bonate Solution, treated With Some charcoal, Split off again by hydrolytic treatment Without filtered and the filtrate is acidified with hydro affecting the acylated sulfonamide group. chloric acid, whereupon the condensation product The Sulfonamides of the benzene Series, Sub separates out. It is drawn off and re-crystallized stituted in the p-position by a nitrogen-contain from alcohol. Melting point 233°C. ing group, may be used as such, or in the form 40 By Saponifying, the free amino compound is of their salts, for example sodium p-nitrobenzene easily obtained. sulfonamide or potassium p-acetylaminobenzene Eacample 3 Sulfonamide. The reaction. With the acylating agents may also be effected as usual in the pres 1 molecule of p-nitrobenzene sulfonamide is ence of bases such as pyridine, dimethyl aniline 45 Suspended in chlorobenzene, treated with 1.2 and SO On, molecules of 3,3-dimethyl acrylic acid and 1 As unsaturated, branched aliphatic carboxylic molecule of phosphorus pentachloride and heat acids may be mentioned 3,6-di-methyl acrylic ed to boiling for Some hours. After the addition acid o- or 3-ethyl crotonic acid, or,6,6-trimethyl of a little Water the chlorobenzene is blown off acrylic acid, cy-methyl-or-allyl acetic acid, iso 50 With steam and the remaining p-nitrobenzene butylidene acetic acid, co-methyl crotonic acid, Sulfone-6,6-dimethyl acrylic acid amide is poured a-isopropyl Crotonic acid and so on. The acids into sodium carbonate solution, filtered from the may be used as such for example in the presence Small amount of unchanged nitrobenzene sulfon of catalysts or in the form of their functional amide, again precipitated with acid and re-crys derivatives, Whilst agents having an acid binding 55 tallized from alcohol, Melting point 155° C. 2,429,207 3 4. Eacample 4 duced, for instance in the case of Example 1, the 50 parts of sodium (or potassium) p-nitro corresponding or,8,8-trimethyl acrylic acid amide benzene sulfonamide are suspended in 150 parts of the melting point 161-162C. by volume of nitrobenzene and treated with 12 Eacample 7 parts of 6,8-dimethyl acrylic acid chloride. The 5 257 parts of p-acetylaminobenzene Sulfonamide temperature rises slowly to 50 C. and is main are suspended in 150 parts by volume of chloro tained at this temperature for 4 hours. Then benzene, treated with 15 parts of 3-ethyl Cro 300 parts of water are added, the whole is made tonic acid chloride and some copper powder and alkaline to litmus, but neutral to phenol 0. refluxed for 4 hours. Then it is cooled some phthaleine and then stirred for 1 hour at 50 what, shaken with dilute sodium carbonate So C. Thereupon the small quantity of unchanged lution and drawn off cold. The chlorobenzene is sulfonamide is filtered off, the filtrate extract blown out of the filtrate by steam, the cooled res ed with ethers and acidified;, p-nitrobenzene idue treated with acid and the separated resin sulfone-6,6-dimethyl acrylic acid amide then separated and washed with Water. It is easily precipitates out in a 70% yield. Melting point 5 soluble in sodium carbonate-solution. 155° C. The acetyl group is split off with dilute Soda. Reduction according to Béchamp's method iye by heating for half an hour on the Water leads to the p-aminobenzene sulfone-6,8-di bath. From a hydrochloric acid solution there methyl acrylic acid amide. is obtained the chlorohydrate of p-aminobenzene Instead of dimethyl acrylic acid there may sulfone-6-ethylcrotonic acid amide with nelting also be used isobutylidene acetic acid, oz-methyl point, 189 C. a-allyl acetic acid or a-methyl crotonic acid; the The isomeric ox-ethyl-crotonic acid compound compounds thus obtained are also colorless and reacts exactly in the same manner as indicated possess similar properties. 25 in the above example. Eacd.imple 5 Eacample 8 535 parts of 4-acetylamino-benzene Sulfon 24.4 parts of 4-carboxy-aminobenzene sulfon amide are mixed in 1000 parts of chlorobenzene amide are treated in a chlorobenzene Solution. with 300 parts of 6,8-dimethyl acrylic acid chlo with the calculated amount of 3,6-dimethyl ride and 5 parts of copper powder and refluxed 30 acrylic acid chloride and 5 parts of copper powder until hydrochloric acid ceases to be given off. and the Whole heated to boiling for 6 hours. After being allowed to cool, the reaction mixture Afterwards it is distilled by steam, the residue is stirred into a 10% sodium carbonate Solution poured into sodium carbonate solution, filtered heated to 50-60° C., then stirred for 72 hour, from the unchanged carbethoxy-aminobenzene cooled down and filtered. The filtrate is distilled 35 sulfonamide and from the copper powder, treated by steam and the condensation product is isolat With a little animal charcoal, filtered and acidified ed therefrom by acidification. With hydrochloric acid. The precipitated 4 The moist crude product drawn off is heated carbethoxyaminobenzene sulfone - 3.8 - dimethyl for 40 minutes to boiling with 1300 parts of 30% 40 acrylic acid amide is re-crystallized from dilute soda lye and 200 parts of water for Saponifica acetOne. tion. Then it is cooled down and the free annino For splitting off the carbethoxy group the Con compound is precipitated with acetic acid and densation product is dissolved in twice normal drawn off. For purification it can be poured into soda, lye and heated for 15 minutes on the Water dilute sodium carbonate solution, then treated bath. By acidifying with acetic acid the 4 With animal charcoal, filtered after SOme time aminobenzene sulfone-g,3-dimethyl acrylic acid and again precipitated out with acetic acid. The amide is obtained. p-aminobenzene -sulfone - 3,5-dimethyl acrylic Instead of the 4-carbethoxy-aninobenzene acid amide melts, when re-crystallized from dilute sulfonamide compound the corresponding carbo alcohol, at 177-178° C. Yield=340 parts. methoxy compound may also be used; further Instead of copper powder other catalysts Such 50 more the chloride of the 6,3-dimethyl acrylic acid as aluminum chloride, ferric chloride, tin tetra is also replaceable by the bromide or by a halide chloride, cupric chloride and so forth maybe used. of another acid cited in the general part of the Eacample 6, Specification. 160 parts of p-acetyl-aminobenzene Sulfon 55 The metal salts of the compounds mentioned amide and 80 parts of anhydrous sodium carbon in the above examples may be made in the usual ate are suspended in 500 parts of chlorobenzene, 36. treated with 100 parts of 3,6-dimethyl acrylic Eacample d. acid chloride and refluxed for 2 hours. The re 254 parts of p-aminobenzene sulfone-g,6-di action mixture is stirred into 1500 parts of Water, 60 methyl-acrylic acid amide are hot dissolved in heated to 60° C., made weakly alkaline with So the required quantity of absolute alcohol. If dium carbonate and the little which is undis necessary, it is hot filtered and the hot, clear solved is sucked off. The aqueous Solution is solution is, while strongly stirred, at once treated separated from chlorobenzene in the separating with a filtered solution of 30 parts of sodium in funnel and then acidified. The separated resin 65 500 parts by volume of absolute alcohol. The which soon solidifies, is drawn off and washed Sodium salt separates out immediately already in With some Water. the hot condition in form of a white powder, After saponifying the acetyl amino group with The whole is, while stirring, cooled down, where dilute soda, lye the dimethyl acrylic acid deriva upon the precipitate is drawn off. The Sodium tive can be obtained in the usual way. 70 Salt is Washed with absolute alcohol, until a test Instead of the 6,3-dimethyl acrylic acid con dissolves in water neutral to phenolphthaleine. pounds used in the Examples to 6 the corre The salt dried in vacuo at 60° C. is obtained in sponding or,3,3-trimethyl acrylic acid compounds, form of a pure white, powder. Yield 265 parts. c-isopropy crotonic acid or derivatives thereof The potassium salt is obtained in exactly the may also be used, whereby there may be pro 75 Sale lane. 2,429,207 5 6 Eacample b wherein Z is a member selected from the group 27.6 parts of the sodium salt prepared accord consisting of H and CH3, and X is a member of ing to the foregoing example are dissolved in the group consisting of H, K, Na, Mg, Zn and Ca. 200 parts by volume of distilled water and 10.1 2. The p-aminobenzene-sulfonamide of the parts of MgCl2.6H2O in a little Water are added 5 formula, thereto. Now the solution is completely evapo C3 rated to dryness in vacuo. The residue is taken up in 300 parts by volume of hot absolute alcohol, the mixture is cooled down and allowed to Stand C3 cold for 4 hours. Then undissolved matters are O which is a colorless compound of melting point filtered off and the filtrate is evaporated to dry 177-1780 C. neSS in vacuo. The magnesium Salt is thus ob 3. The p-aminobenzene-sulfonamide of the tained in form of an amorphous mass; it is easily formula Soluble in water. Eacample c 5 CH, 50 parts of p-aminobenzene sulfone-3,6-di methyl acrylic acid amide are dissolved in the H.N-(D-so-NE-00--CCC3 C3 calculated quantity of caustic soda lye of 1 per Which is a colorless compound of melting point cent strength and treated with a clear solution 161-162° C. of 14 parts of zinc chloride in 100 parts by volume 20 HENRY MARTIN. of Water. The Solution is allowed to Stand for 1. RUDOLF ERT. hour, the zinc salt separated Out is drawn off and washed several times with distilled Water. Fi REFERENCES CTE) nally it is dried in vacuo at 60° C. and obtained The following references are of record in the in form of a white, light powder which is difficultly 25 file of this patent: Soluble in Water. The calcium salt is obtained in the same form FOREIGN PATENTS according to the usual process. Number Country Date What we claim is: 111,230 Australia ------Aug. 22, 1940 1. A therapeutically active p-aminobenzene 30 Sulfonamide of the formula, OTHER REFERENCES CrOSsley et al., Jour. Am. Chem. Soc., vol. 61, CBIs pp. 2950-2955, Oct. 1939. Schweizerische Medzinische Wochenschrift No. Z CH3 35 31, Aug. 2, 1941, pp. 901, 905 and 906.