Patent GB-620654-A (GB)
Title: A process for the preparation of sulphonamide derivatives of 2-amino-thiazole
Filed: 1940-07-22
Abstract: Sulphonamide derivatives of 2-amino-thiazole are obtained by treating thioureides A.Y.SO2 NHCSNH2 with a  - halogen - aldehydes or -ketones, their acetals or ethers of their halogenhydrins, or a -halogenated cyclic ketones, or di-or poly - a  - halogeno - oxo compounds or a -halogeno-oxo-carboxylic acids or esters thereof, preferably in the presence of an acid binding agent such as pyridine or other tertiary heterocyclic base.  In the above formula, A is a p-substituent of benzene-sulphonyl or a 2-substituent of pyridine and is an amino, alkylamino, acylamino, or acylated alkylamino group, or a nitrogen-containing group such as an acylamino, acylated alkylamino, nitro or azo group which is convertible by subsequent desacylation or reduction into an amino or mono-alkylamino group and Y is a benzene or pyridine nucleus.  The thioureides are obtained by the elimination by alcoholysis preferably with absolute methyl or ethyl alcohol in the presence of an acid catalyst, e.g. hydrochloric acid of the a -alkoxy-alkyl group from an S-(a -alkoxy-alkyl) ether of an iso-thiourea which has been acylated with a benzene sulpho-halogenide containing one of the above-mentioned convertible groups, e.g. p-acetylamino-benzenesulphonyl chloride or a pyridine-sulphonyl halogenide, e.g. 2 - acetamino - pyridine - 5 - sulphonyl bromide. S-(ethoxy-ethyl), S-(methoxy-methyl) and S-(ethoxy-methyl) ethers are mentioned and p-acylamino- or p-nitro-benzenesulpho-alkoxy methyl-iso-thioureas preferred, the alkoxy-methyl ethers being preferably used as their salts in the presence of an acid binding agent such as pyridine, sodium acetate or alcoholate.  The free p - amino - benzenesul - phonyl thiourea may be obtained from the corresponding p-substituted thiourea before reaction with the a  - halogeno compound.  a -Halogeno reactants instanced are chloro-acetone, 2-chloro-butanone-3, a -chloro-cyclohexanone, sym-mono-chloro- or mono-bromoacetylacetones, mono-bromo-di-acetyl-monoxime, chloro-acetaldehyde, a -bromo-propionaldehyde, the di-ethyl-acetal of chloro-acetaldehyde, 1.2-dichloro-ethyl-ether, a -chloro-a -aceto-acetic acid ethyl ester or chloro-pyruvic acid or its esters, chlor-acetic acid and ethyl ester, bromo- or chloro-malonic acid di-ethyl ester and chloro-cyanacetic acid ester.  Preferably, halogen-ketones are used which contain halogen, oxy, alkoxy or acyloxy groups, e.g. sym-dichlor-acetone or the a -alkoxy-, a 1-chloroacetones.  In examples, p-acetyl-amino-benzene-sulphonyl-thiourea is treated with chloroacetone in the presence of (1) 80 per cent alcohol; (2) pyridine and 80 per cent alcohol; (3) and (4) pyridine to yield p-acetamino-benzenesulphonyl-2-amino-4-methyl-thiazole which is hydrolysed with aqueous sodium hydroxide to the p-amino-compound, and in the presence of pyridine with (5) a .b -di-chloro-di-ethyl ether yielding p-acetamino-benzenesulphonyl-2-amino-thiazole; (6) ethyl-a -chloro-acetoacetate yielding 2-(p-acetylamino-benzenesulphamido) -4-methyl-thiazole-5-carbethoxylate which with dilute sodium hydroxide yields 2 - (p - amino - benzenesulphamido) - 4 - methyl - thiazole - 5 - carboxylic acid sodium salt and with absolute alcohol containing hydrogen chloride yields 2-(p-amino-benzenesulphamido) - 4 - methyl - 5 - carbethoxy - thiazole hydrochloride which is converted to the free base by treatment with sodium acetate; (8) sym-mono-chloro-acetyl-acetone to give 2-(p-acetamino-benzenesulphamido) - 4 - methyl - S - aceto-thiazole which with aqueous sodium hydroxide yields the corresponding p-amino-compound obtainable also by condensing monochloro-acetyl-acetone with p-amino-benzene-sulphonyl-thiourea; (9) mono-bromo-diacetylmonoxime to give 2-(p-acetylamino-benzenesulphamido)-4-aceto-thiazole-oxime which with aqueous sodium hydroxide yields 2-(p-amino-benzenesulphamido) - 4 - aceto - thiazole; (10) a  - chloro - cyclohexanone yielding 4.5 - tetra - methylene - 2 - (p - acetylamino - benzenesulphamido)-thiazole which with aqueous sodium hydroxide gives the corresponding p-amino compound which may be obtained directly from p - amino - benzenesulphonyl - thiourea and the above ketone; (11) ethyl chloro-acetate to give p-acetylamino-benzenesulphonyl - 2 - amino - 4-hydroxy-thiazole; (13) chloro-malonic diethyl ester to give a mixture of 4-hydroxy- and 4-ethoxy - p - acetamino - benzenesulphonyl - 2 - amino-5-carbethoxy-thiazole; and (15) symdichloro-acetone to give p-acetamino-benzenesulphonyl - 2 - amino - 4 - chloromethyl - thiazole which with (a) absolute alcohol and hydrogen chloride yields the hydrochloride of the corresponding p-amino compound from which the free base is obtained by treatment with ethyl acetate and aqueous sodium acetate and is also prepared from p - amino - benzene - sulphonyl - thiourea and sym-dichloro-acetone or with (b) aqueous hydrochloric acid yields p-aminobenzenesulphonyl-2-amino-4-hydroxymethylthiazole, in (7) p - amino - benzenesulphonyl - thiourea is treated with ethyl a -chloro-acetoacetate to give 2-(p-amino-benzenesulphamido)-4-methyl-5-carbethoxy-thiazole, probably an isomer of the product of (8), in (12) with ethyl chloro - acetate to give p - amino - benzenesulphonyl-2-amino-4-hydroxy-thiazole and in (14) with diethyl bromo-malonate to yield mixed 4 - hydroxy- and 4 - ethoxy - p - acetylamino - benzenesulphonyl - 2 - amino - 5 - carbethoxy - thiazole.  It is stated that in (6) and (7) methyl, butyl, amyl or benzyl esters of chloro-acetic acid may be used in place of the ethyl ester to give the corresponding carbalkoxy-thiazole and that in (4), (7) and (10) p-nitro-benzene-sulphonylmay replace p-acetylamino-benzenesulphonyl-thiourea to give the corresponding p-nitro-substituted thiazole, p-nitro-benzenesulphonyl - 2 - amino - 4 - methyl - thiazole being hydrogenated in alcohol with a palladium catalyst to the corresponding p-amino compound.  It is also stated that p-acetylaminobenzenesulphonyl-thiourea may be condensed with 3-chloro-butanone-2, 1-chloro-butanone-2, 1.1-dichloro-acetone, 4-amino- or 4-acetamino-a -chloro-acetophenone, or 2-chloro-4-methylcyclohexanone to give respectively p-acetylamino - benzenesulphonyl - 2 - amino- -4.5 - di - methyl-thiazole, -4-ethyl-thiazole, -4-methyl-5-chloro-thiazole, -4-(p1-amino-phenyl)- or -4-(p1-acetylamino - phenyl) - thiazole, or 4.5 - tetra - methylene - 2 - (p - acetylamino - benzenesulph - amido)-thiazole in which the third methylene group attached to the 4 position is substituted with a methyl group, the first three of these products are converted to the corresponding free p-amino compound and the free p-amino compounds of the fourth and fifth may be obtained from the corresponding free p-aminobenzene - sulphonyl - thiourea with the appropriate ketone.  Other condensations instanced are p - amino - benzenesulphonyl - thiourea with 4-chloroaceto-pyro-catechin or a -methoxy-a 1-chloro-acetone to give p-amino-benzenesulphonyl - 2 - amino - 4 -(31,41 - dihydroxy - phenyl) - thiazole and 4-methoxymethylthiazole respectively, and 2-acetamino-pyridine-5-sulphonylthiourea with a -chloro-acetaldehyde or chloroacetone to give 2-acetamino-pyridine-5-sulphonyl-2-amino-thiazole or 4-methyl-thiazole respectively.  Practical details are given for the preparation of the thiourea starting materials, e.g. p-acetylamino- and p-nitro-benzenesulphonyl-thiourea and 2-acetamino-pyridine-5-sulphonyl-thiourea, by methods outlined above and for the desacylation of p-acetamino-benzene-sulphurylthiourea to the corresponding free p-amino compound.  Specification 544,215 is referred to.