DE1133390B - Process for the production of quinazolone derivatives - Google Patents

Description

Process for the production of quinazolone derivatives It has been found that valuable quinazolone derivatives are obtained when in a manner known per se 3-Carbalkoxyaminochinazolones, which have one or two amino groups in the benzene ring and also substituted by halogen atoms, lower alkyl or alkoxy groups can be, with pyrocarbonic acid alkyl esters, alkali metal cyanates or acetylating Reacts derivatives of acetic acid.

Some of the starting materials are or will be known from the literature produced by methods known per se.

The reaction is carried out in organic solvents or optionally also made in water. The products of the process are generally colorless and well crystallized. They dissolve in dilute alkalis.

The procedural products are sedative or hypnotic and in part also effective as a muscle relaxant. The combination of the two properties mentioned makes them particularly valuable. So you provide valuable sleeping pills, if necessary also represent anesthetics.

In order to demonstrate the superiority of the process products over known compounds of a similar structure with the same mode of action, the 2-methyl-3,6-bis (carbethoxyamino) quinazolone (4) (I) obtainable according to the invention was used. with the known 2-methyl-3- (4'-chloro-.2'-methyl-phenyl) -quinazolon- (4) (II) compared. The following results were achieved with regard to toxicity and narcotic effectiveness: Mouse per os, mg / kg ratio DL "[ NDGO DLso: NDso I 3000 '360 8.3 (2300 to 4000) (300 to 430) 1I 530 233 2.3 (445 to 630) (199 to 272) The comparative preparation II is several times more toxic than the compound I. It is particularly important that the ratio of lethal to narcotic dose for both comparative substances is only 1: 2.3, whereas with compound I it is 1: 8.3. The somewhat stronger narcotic effectiveness of the comparator preparation is thus devalued by the considerably stronger toxicity, the "therapeutic range" is several times smaller.

In addition, the compound I has a strong muscle relaxing effect, the cause of which is an inhibition of the activity of certain nerve cells in the spinal cord. When administered intravenously to cats at 2 to 4 mg / kg of Compound I the spinal cord reflexes already weakened. From the connection II are about 5 to 8 mg / kg is required for the same effect. If the connection is more toxic II its muscle-relaxing effect is weaker than that of the compound I.

When used therapeutically as a sleep aid, one would benefit from the compound 1I take lower doses than compound I because of its higher toxicity have to and thereby the already less muscle-relaxing effect even further Reduce. The better muscle relaxing effect of the compound I is considered to be special Advantageous for their use as a sleep aid because of the relaxation of the muscles favors the onset of sleep.

Example 1 To a suspension of 26.2 parts of 2-methyl-3-carbäthoxyamino-6-amino-quinazolon- (4) 18 parts of ethyl pyrocarbonate are added to 100 parts of alcohol. One warms them up Mix carefully to 55'C, the approach clear with evolution of carbon dioxide goes into solution. A small sample of this solution is mixed with water and up to Triturated at the beginning of crystallization. With these seed crystals the frozen Inoculated main amount. The 2-methyl-3,6-bis (carbethoxyamino) -quinazolon- (4) separates analytically pure. The compound melts at 192 ° C; Yield: 28.5 g (85%) the theory). It is in dimethylformaemide and glycol monomethyl ether acetate soluble. In contrast to the starting material, it can no longer be diazotized.

In an analogous manner, from 2-methyl-3-carbäthoxyamino-5-aminochinazolon- (4) 2-methyl-3,5-bis (carbethoxyamino) quinazolone- (4); M.p. 169 to 170 ° C; Yield: 810/0 of theory.

The 2-methyl-3-carbäthoxyamino-6-amino-chiliazolon- (4) used as starting material is made as follows: 40 parts of 2-methyl-3-carbäthoxyamino-6-nitro-quinazolnn- (4) (can be prepared from N-acetyl-5-nitro-anthranous acid anhydride by various methods), dissolved in 150 parts of tetrahydrofuran, 5 to 10 parts of Raney nickel are added Catalytically hydrogenated at 27 to 30 ° C and about 20 atmospheres in an autoclave. The calculated Amount of hydrogen is absorbed in 230 minutes. The approach is another 30 minutes stirred, but the hydrogen uptake has ended. The contents of the autoclave are increased heated to 45'C after opening and the catalyst was filtered off. The 2-methyl-3-carbethoxyamino-6-amino-quinazolon- (4) crystallizes out in long white needles, which recrystallize from ethyl acetate or alcohol can be; M.p. 189 to 190 ° C; Yield 33 parts.

Example 2 26.2 parts of 2-methyl-3-carbethoxyamino-6-aminochinazolon- (4) are in a mixture of 25 parts of glacial acetic acid and 60 parts of acetic anhydride Heated to 80 ° C for 2 hours. The clear solution is poured onto 300 parts of ice, the 2-methyl-3-carbethoxyamino-6-acetyl-amino-quinazolone- (4) precipitates. The 2-methyl-3-carbäthoxyamino-6-acetylamino-quinazolon- (4) is filtered off with suction, washed with water and recrystallized from alcohol. It is in dilute sodium hydroxide solution soluble; M.p. 191 to 192 ° C; Yield (after purification) 14 to 16 parts.

Example 3 Dissolve 26.2 parts of 2-methyl-3-carbethoxyamino-6-amino-quinazolon- (4) in a mixture of 120 parts of water and 14 parts of concentrated hydrochloric acid and gives an (excess of solid sodium cyanate (about 8 to 10 parts) in portions. Towards the end of the reaction, the 2-methyl-3-carbäthoxyamino-6-carbamylaminoquinazolone (4) crystallizes the end. The compound can be recrystallized from methanol; it melts at 202 up to 204 ° C; Yield: 70 to 85% of theory.

Example 4 As described in Example 1, the following compounds can also be reacted with ethyl pyrocarbonate in alcohol; the process products are obtained in yields of 70 to 850 /, of theory. F. 200 to 202 ° C (made from 6-nitro-2-aminobenzoic acid hydrazide-u) -carboxylic acid ethyl ester by ring closure with formic acid and catalytic reduction) F. 149 ° C (produced by catalytic reduction of the corresponding nitro compound with a melting point of 149 ° C) Mp 174-175 ° C F. 216 to 218'C (produced by catalytic reduction of the corresponding nitro compound with a melting point of 153 to 155 ° C) F. 194 to 195 ° C. Example 5 52.4 parts of 2-methyl-3-carbäthoxyamino-7-aminochinazolon- (4) are boiled with 40 parts of ethyl pyrocarbonate in 400 parts of alcohol until the starting material has dissolved. The 2-methyl-3,7-bis (carbäthoxyamino) - quinazolone - (4) slowly crystallizes out. It is purified by recrystallization from chlorobenzene or from alcohol. In the pure state, it melts at 197 to 198 ° C., yield: 70 to 85% of theory.

The required raw material is prepared as follows: One boils 4-Nitro-2-aminobenzoic acid with excess acetic anhydride to obtain N-acetyl-4-nitro-anthranilic anhydride from melting point 143 to 144 ° C. This is with hydrazine monocarboxylic acid ethyl ester heated in glycol monomethyl ether acetate for 4 hours at 100.degree. From the solution obtained the 2-methyl-3-carbäthoxyamino-7-nitro-quinazolone- (4) separates from the melting point 146 to 147'C. It is in the presence of Raney nickel in tetrahydrofuran at 30 Catalytically hydrogenated up to 60 ° C. The colorless 2-methyl-3-carbethoxyamino-7-amino-quinazolone- (4) melts at 211 to 212 ° C.

Claims (1)

PATENT CLAIM. Process for the preparation of quinazolone derivatives, characterized in that, in a manner known per se, 3-carbalkoxyaminoquinazolones which carry one or two amino groups in the benzene ring and can also be substituted by halogen atoms, lower alkyl or alkoxy groups, with alkyl pyrocarbons, alkali metal cyanates or acetyherent derivatives the acetic acid converts.