DE1111195B - Process for the preparation of 4-hydrazino-uracils - Google Patents

Description

Process for the preparation of 4-hydrazino-uracils The invention relates to a process for the preparation of 4-hydrazinouracils, which are useful as bactericidal agents and as intermediates in the preparation of therapeutically active compounds. According to the process for the preparation of 4-hydrazino-uracils of the general formula in which R denotes an optionally substituted aryl radical and R denotes a hydrogen atom or the methyl radical, a uracil of the general formula wherein R has the meaning given above and X is a halogen atom, e.g. B. indicates a chlorine atom, or a methylsulfonyl or a phenylsulfonyl radical, or one of its salts with a hydrazine of the general formula H, N-NH-R wherein R has the meaning given above, or one of its salts reacts at elevated temperature.

An example of an aryl group suitable for R is a phenyl group mentioned, which, if desired, by halogen atoms, such as chlorine, bromine or fluorine atoms, or by a low molecular weight alkyl group, e.g. B. a methyl radical substituted can be.

The reaction can usually be carried out in that the Reaction ingredients in an inert medium, e.g. B. in an aqueous medium after Desired in the presence of an acid binding agent, e.g. B. an excess of hydrazine, a tertiary organic base, e.g. B. triethylamine, tri-n-butylamine or triethanolamine, or an inorganic acid-binding agent, e.g. B. sodium carbonate, or in Presence of a buffering agent, e.g. B. sodium acetate, are heated together.

As mentioned above, the pyrimidine derivatives have the present Invention bactericidal properties and are used as bactericidal in infections of the Urinary tract particularly valuable. The pyrimidine derivatives prevent the growth of microorganisms, z. B. Streptococcus faecahs, Streptococcus pyogenes, Streptococcus agalactiae, Streptococcus pneumoniae and Staphylococcus aureus. The derivatives are effective when taken orally administered.

The known compound 5-hydrazino-uracil has no useful antibacterial properties. This is shown in the table below, which in the usual way indicates the lowest concentrations of 4-phenylhydrazino-uracil (compound A) and 5-hydrazinouracil (compound B) which completely inhibit the growth of the organism in question in vitro. Smallest inhibiting effective concentration Connection Al Connection B Streptococcus pyogenes 1: 729000 1: 3000 Staphylococcus aureus ... 1 : 6.5 - 106 1: 1000 The present invention is illustrated by the following examples in which parts are by weight. Example 1 A mixture of 1.46 parts of 4-chloro-uracil, 2 parts of phenylhydrazine and 100 parts of water is refluxed for 2 hours in a nitrogen atmosphere. The crystalline precipitate that forms on cooling is collected by filtration and washed with water and a little cold ethanol. 4-Phenylhydrazino-uraeil is obtained in the form of light red crystals which decompose at 283 to 284 ° C. 83 0 /, yield.

Example 2 A mixture of 14.6 parts of 4-chloro-uracil, 11 parts of phenylhydrazine, 50 parts of sodium acetate trihydrate and 1000 parts of water is refluxed for 16 hours in a nitrogen atmosphere with stirring and then cooled and filtered. The solid residue is washed with water and thus gives 4-phenylhydrazino-uracil, which decomposes at 283 to 284 ° C. 73 0/0 yield.

Example 3 A mixture of 1 part of 4-methanesulfonyluracil, 1 part of phenylhydrazine and 5 parts of water is refluxed in a nitrogen atmosphere for 1 hour and then cooled. The solid residue is washed with water and thus gives 4-phenylhydrazino-uracil, which decomposes at 283 to 284'C. 700 /, yield.

Example 4 A mixture of 1 part of 4-benzenesulfonyluracil, 0.8 part of phenylhydrazine and 250 parts of water is refluxed in a nitrogen atmosphere for 16 hours and then cooled and filtered. The solid residue is washed with water and thus gives 4-phenylhydrazino-uracil, which decomposes at 283 to 284'C. 50 %, yield.

The 4-benzenesulfonyl uracil used as starting material can be prepared in the following manner: A mixture of 1.46 parts of 4-chlorouracil, 2.8 parts of sodium benzenesulfinate dihydrate and 50 parts of water is refluxed for 1 hour and then cooled and filtered. The solid residue is washed with water and thus gives 4-benzene-sulfonyl-uracil, which decomposes at 278 to 280 ° C.

Example 5 A mixture of 14.6 parts of 4-chloro-uracil, 18 parts of p-fluorophenylhydrazine hydrochloride, 20 parts of sodium acetate trihydrate and 1000 parts of water is heated under reflux for 2 hours in a nitrogen atmosphere with stirring and then cooled and filtered. The solid residue is washed with water and thus gives 4-p-fluorophenylhydrazino-uraeil, which decomposes at 285 to 290.degree. 560 /, yield.

Example 6 A mixture of 1.46 parts of 4-chloro-uracil, 3.58 parts of p-chlorophenylhydrazine hydrochloride and a solution of 0.8 part of sodium hydroxide in 100 parts of water is refluxed for 2 hours in a nitrogen atmosphere and then filtered . The solid residue is washed with water and gives 4-p-chlorophenylhydrazino-uracil, which turns dark at 300'C and decomposes above 340'C. 63 l) /, yield.

Example 7 A mixture of 7.3 parts of 4-chloro-uracil, 10.6 parts of 2,4 - dichlorophenylhydrazine - hydrochloride, 25 parts of sodium acetate trihydrate and 500 parts of water is heated for 5 hours under reflux in a nitrogen atmosphere under stirring and then cooled and filtered. The solid residue is washed with water and with acetone and gives 4- (2 ', 4'-dichlorophenylhydrazino) -uraeil, which decomposes above 350'C. 3501, yield. Example 8 A mixture of 2 parts of 4-chloro-uracil, 3 parts of p-bromophenylhydrazine hydrochloride, 5 parts of sodium acetate and 150 parts of water is refluxed in a nitrogen atmosphere for 16 hours and then cooled and filtered. The solid residue is washed with water and with ethanol to give 4-p-bromophenylhydrazinouraeil, which decomposes above 320.degree. 830 /, yield.

Example 9 A mixture of 7.3 parts of 4-chloro-uracil, 10 parts of o-tolylhydrazine hydrochloride, 20 parts of sodium acetate trihydrate and 500 parts of water is refluxed in a nitrogen atmosphere for 4 hours and then cooled and filtered. The solid residue is washed with water and with alcohol and thus gives 4-o-tolylhydrazino-uracil, which decomposes above 340.degree. 670/0 yield.

The process described above is repeated, but the o-tolylhydrazine hydrochloride used as the starting material is replaced by m-tolylhydrazine hydrochloride. This gives 4-m-tolylhydrazinouracil which decomposes at 205 to 210 ° C. 5001,) yield.

The process described above is repeated, but instead of the o-tolylhydrazine hydrochloride used as the starting material, p-tolylhydrazine hydrochloride is used. The result is 4-p-tolylhydrazino-uracu, which decomposes at 277 to 278 ° C. 740 /, yield.

Claims (2)

PATENT CLAIMS: 1. Process for the preparation of 4-hydrazinouracils of the general formula wherein R denotes an optionally substituted aryl radical and R denotes a hydrogen atom or the methyl radical, characterized in that a urea of the general formula in which R has the meaning given above and X is a halogen atom or a methylsulfonyl or phenylsulfonyl radical, or one of its salts with a hydrazine of the general formula H, N - NH - R in which R has the meaning given above, or one of its salts Reacts at elevated temperature. 2. The method according to claim 1, characterized in that the reaction components are heated together in an inert medium, if desired in the presence of an acid-binding agent or a buffer substance. 3. The method according to claim 2, characterized in that an excess of the hydrazine component or a tertiary organic base or an inorganic acid-binding agent is used as the acid-binding agent. Considered publications: "Beilstein's Handbook of Organic Chemistry", 11th supplementary work, Vol. 24, p. 266; "Liebigs Annalen der Chemie", Vol. 258 (1890), p. 359; Journal of the Chemical Society (1955), pp. 3478 to 3481; "Chemical Abstracts", Vol. 50 (1956), Col. 4976f.