Patent GB-541958-A (GB)
Title: The manufacture of derivatives of sulphonamides
Filed: 1938-12-08
Abstract: 541,958. Sulphonacylamido compounds ; a<SP>7</SP>o dyes. SCHERING AKT.-GES. Dec. 8, 1938, No. 35882. Convention date, Feb. 2. Samples furnished. [Class 2 (iii)] Sulphonacylamido compounds of the formula R.SO  2 .NH.CO.R<SP>1</SP>, where R<SP>1</SP> represents a hydrocarbon residue and R represents a benzene ring substituted in the p-position by the following groups : (1) amino, (2) acylamino, (3) p-aminobenzenesulphonamido, (4) p-acylaminobenzenesulphonamido, (5) 2<SP>1</SP>:4<SP>1</SP>-diaminobenzeneazo, or (6) benzylamino, are prepared by introducing the group COR<SP>1</SP> into compounds of the formula R.SO 2 NH 2  bv known acylation methods, e.g. by use of acid chlorides or anhydrides. When group (1), (3) or (5) is present, it will be acylated at the same time, and the product may then be subjected to partial hydrolysis to 'restore the said group ; similarly, products containing groups (2) or (4) may be partially hydrolysed to products containing groups (1) or (3). Instead of group (1), a nitrogen-containing group may be present and the product then treated to convert the said group into group (1) ; also products containing group (1) may be diazotized and coupled with m-phenylenediamine to produce products containing the group (5). Before acylation, the amino group may be protected by a group, such as carbomethoxy or carbobenzyloxy, which can readily be split off again. Alternatively, the sulphonacylamido compounds, except those containing group (5), may be produced by introducing the residue R.SO 2  into compounds of the formula NH 2 .CO.R<SP>1</SP> by methods known to be capable of introducing this residue into amines, e.g. by use of the corresponding benzene sulphonic halides. This method is only applicable, however, when groups (2), (4) and (6) are present or when group (1) is replaced by a nitrogen-containing group ; in the case where groups (2) or (4) are present, the product may be partially hydrolysed, whilst when a nitrogen-containing group is present, it may be subsequently converted into the amino group. As nitrogen-containing groups, the nitro and azo groups are mentioned, the amino group then being formed either by reduction or by reductive splitting. The sulphonacylamido products may be converted into their alkali or alkaline earth metal compounds by treatment with alkali or alkaline earth metal oxides, hydroxides or carbonates, and the alkali metal compounds transformed into heavy metal compounds-of which those of gold, silver and mercury are mentioned-by interaction with heavy metal salts. The sulphonacylamido products and their metal derivatives are useful as therapeutic agents and as intermediates for the manufacture of pharmaceutical products and plant protecting agents. Examples describe the preparation of (1) 4- aminobenzenesulphonacetylamide by treating 4-amino or 4-acetylaminobenzenesulphonamide with acetic anhydride or acetyl chloride and partially hydrolysing the diacetyl product with sodium hydroxide solution ; the same product is obtained by re-acting 4-acetylaminobenzenesulphonic acid chloride with acetamide and partially hydrolysing ; the propionylamide is similarly obtained from 4-aminobenzenesulphonamide using propionic anhydride ; (2) 4- aminobenzenesulphonbenzoylamide by reacting 4-acetylaminobenzenesulphonamide with benzoyl chloride and partially hydrolysing with sodium hydroxide solution ; (3) 4-benzylaminobenzenesulphonacetamide by heating 4-benzylaminobenzenesulphonamide with acetic anhydride ; (4) 4:4'-aminobenzene-sulphonamidobenzene-sulphonacetylamide by treating the corresponding sulphonamide with acetic anhydride and partially hydrolyzing the diacetyl product; (5) 4-acetylsulphonamido-2<SP>1</SP>:4<SP>1</SP>-diamino-1:1<SP>1</SP>-azobenzene either by diazotizing 4-aminobenzenesulphonacetamide and coupling with m-phenylenediamine, or by acetylating 4-sulphonamido-2*: 4<SP>1</SP>-diamino-1 : 1<SP>1</SP>-azobenzene and partially hydrolyzing. The preparation of p-aminobenzenesulphonacetamide by acetylation of p-nitrobenzenesulphonamide followed by reduction is described. Specifications 417,872, 462,765, 474,423 and 482,576 are referred to. The samples furnished under Sect. 2 (5) comprise (1) 4-aminobenzenesulphonacetylamide prepared by treating carbanilic acid ethyl ester with chlorsulphonic acid, introducing ammonia into an ethereal solution of the resulting carbethoxy-sulphanilic acid chloride to give the amide, heating the latter with acetic acid and acetyl chloride, and finally splitting off the carbethoxy group with sodium hydroxide solution; (2) 4-aminobenzenesulphonbutyrylamide by heating 4-carbethoxysulphanilic acid amide with butyric acid anhydride and hydrolyzing off the carbethoxy group ; (3) 4-aminobenzenesulphonpropionylamide by the same process as (2) using propionic acid anhydride ; (4) 4-aminobenzenesulphonphenacetylamide by the process of (2) using phenacetyl chloride ; (5) sodium salt of 4-aminobenzenesulphonacetamide by dissolving the amide in sodium hydroxide solution and precipitating with alcohol; (6 and 7) calcium and barium salts of 4-aminobenzenesulphonacetamide by dissolving the amide in water with calcium carbonate and barium hydroxide respectively and evaporating to dryness; (8) calcium salt of 4-aminobenzenesulphonpropionylamide by adding calcium carbonate to an aqueous solution of the amide and evaporating the filtrate to dryness ; (9) mercury salt of 4-aminobenzenesulphonacetamide by re-acting the sodium salt with mercury acetate in aqueous solution. The Specification as open to inspection under Sect. 91 describes the manufacture of compounds of the formula R.SO 2 .NHX, in which R indicates an aromatic, heterocyclic or aromaticheterocyclic residue containing at least one nuclear-bound amino group or group.convertible thereinto and X represents any acyl residue, either by introducing the acyl group into compounds R.SO 2 .NH 2  or by introducing the residue R.SO 2 - into compounds NH 2 X. The first method includes the inter-action of an acylating agent with the silver compound of the sulphonamide: When the sulphonamide starting material contains a nitro, nitroso, azo, azoxy or hydrazo group, it may subsequently be converted into the amino group ; similarly halogen may be so converted with ammonia, acylamino and azomethine by hydrolysis, and acid amide or hydrazide groups by known degradation reactions. For the second method, metal compounds of the amides, e.g. the silver compounds, may be used ; also alkali or alkaline metal salts of sulphonic acids may be reacted with acid amides in the presence of such compounds as sulphuryl chloride or the sulphonyl chlorides which form anhydrides or chlorides from the sulphonates. This method also includes the inter-action of sulphinic acids or their salts with acid amides which contain a halogen attached to nitrogen. Specified starting materials include p-aminobenzenesulphonamidobenzene-m-sulphonamide, azo dyestuffs of the type of 4-sulphonamido-2<SP>1</SP>:4<SP>1</SP>-diamino-1:1<SP>1</SP>- azobenzene and the glucosides of p-aminobenzenesulphonamide. The sulphonacylamido products may be converted into their metal derivatives either directly or by double decomposition ; silver, aluminium and magnesium compounds are specifically referred to in addition to those above. Salts may also be formed with organic bases, e.g. alkylamines, alkanolamines, such as ethanolamines, pyridine, aniline, 1-phenyl-2 : 3-dimethyl-4-dimethylamino-5-pyrazolone, morphine and quinine. The sulphonacylamido products containing free amino groups may be diazotized and coupled with aromatic, heterocyclic or aromatic-heterocyclic bases ; it is stated that the same products can be obtained by condensing in customary manner an aromatic, heterocyclic or aromatic-heterocyclic nitro compound which contains a nuclear-bound basic nitrogen atom, or by reducing corresponding azoxy compounds or by. de-hydrogenating corresponding hydrazo compounds. The Specification contains additional examples describing the preparation of (1) 3- nitrobenzenesulphonacetamide by heating 3- nitrobenzenesulphonamide with acetic anhydride ; the product may be reduced to the amino compound ; (2) 4-acetylaminobenzenesulphonamido - 3<SP>1</SP> - benzenesulphonacetylamide by reacting 3-aminobenzenesulphonamide with 4-acetylaminobenzenesulphonic acid chloride, splitting of the acetyl group and treating the product with acetic anhydride ; by careful saponification, the corresponding 4-amino compound is obtained ; (3) 4-aminobenzenesulphonacetylamide by treating sulphanilamide in sodium hydroxide solution with benzylchlorocarbonic ester, boiling the 4-N-carbonic acid benzyl ester-aminobenzenesulphonamide with acetic anhydride and splitting off the N- substituent from the resulting sulphonacetylamide either by treatment in a'cohol with hydrogen in presence of palladium black or by heating with sodium hydroxide solution; (4) 4-aminobenzenesulphonacetylamide by heating 4 - carbomethoxy - aminobenzenesulphonamide, prepared by grinding sodium carbomethoxysulphanilate with phosphorus pentachloride and treating with ammonia, with acetic anhydride and acetyl chloride and splitting off the carbomethoxy group ; (5) 4-aminobenzenesulphonacetamide-glucoside by boiling 4-aminobenzenesulphonacetamide with glucose in alcohol solution ; (6) 4:4<SP>1</SP>-disulphonacetamide-diphenylurea by introducing phosgene into a sodium hydroxide solution of 4-aminobenzenesulphonacetamide; (7) 4-aminobenzenesulphon-nicotoylamide by heating 4-carbethoxy-sulphanilic acid amide with nicotinic acid chloride and removing the carbethoxy group with sodium hydroxide solution; (8) 4-aminobenzenesulphoncrotonylamide by the process of (7) using crotonic acid and crotonyl chloride ; (9) 4- acetylaminobenzenesulphon - p - nitrobenzoylamide by treating the sulphonamide with 4-nitrobenzoyl chloride ; (10) 4-