Patent GB-807687-A (GB)
Title: Phenoxazone-dicarboxylic acid derivatives
IPC: C07D265/38
Filed: 1956-10-10
Abstract: The invention comprises compounds of the general formula <FORM:0807687/IV (b)/1> where X represents an amino or hydroxy radical; and R and R1 are identical and each represents a carboxyl or a carboalkoxy radical or a carbonyl radical linked in acid-amide fashion to an alkylamino group, an amino acid, an amino acid ester, an alkamino acid, an acetoxyamino acid, an acetoxyamino acid ester, a polypeptide, a polypeptide ester, a peptidelactone or a polypeptidelactone residue, and the preparation of those compounds of the above general formula wherein X is an amino group by subjecting a 4-methyl-3-hydroxy-2-aminobenzoic acid or an N-carbonyl substituted amino acid derivative thereof to oxidation. In the examples (in which the compound of the general formula above wherein X is -NH2 and R and R1 are -COOH is referred to as Actinocin, the corresponding -OH compound as Desamino-actinocin, and the divalent acid radicals derived therefrom as Actinocyl and Desamino-actinocyl respectively): Actinocin is prepared by dissolving 4-methyl-3-hydroxy-anthranilic acid in N/10 caustic soda (pH = 9.5) and oxidizing it with M/10 potassium ferricyanide solution, the resulting solution being at pH 3.5.  Alternatively actinocin is prepared by oxidation of a solution of 4-methyl-3-hydroxyanthranilic acid in aqueous ammonium carbonate by a rapid stream of air.  Methylation of actinocin by methyl iodide and silver oxide yields actinocin dimethyl ester which is also prepared by oxidation of a chloroformic solution of the methyl ester of 4-methyl-3-hydroxyanthranilic acid with yellow mercuric oxide. From the correspondingly substituted anthraacids the following compounds are prepared by oxidation in ammonium carbonate solution with air: N,N1-actinocyl-bis-aminoethanoic acid dimethyl ester, N,N1-actinocylbis - O - acetyl - threonine dimethyl ester, N,N1 - actinocyl - bis - glutathion - tetramethyl ester, N,N1 - actinocyl - bis - p - aminobenzoyl-b  - alanylsarcosine diethyl ester, N,N1-actinocyl - bis - p - aminobenzoyl - glycylsarcosine diethyl ester, N,N1 - actinocyl - bis - p-aminobenzoyl - glutamic acid tetraethyl ester, N,N1 - actinocyl - bis - d  - amino - g  - valerolactone and N,N1 - actinocyl - bis - ethylamine.  Also by oxidation with ferricyanide are prepared: N,N1-actinocyl-bis-aminoethanoic acid (also prepared from its ethyl ester by hydrolysis with sodium hydroxide solution), N,N1-actino-cyl - bis - glycylvaline, N,N1 - actinocyl - bisglycylvalylproline and N,N1-actinocyl-bis-threonine.  In examples of compounds of the general formula above wherein X is OH, desamino-actinocin dimethyl ester is prepared by refluxing actinocin dimethyl ester with glacial acetic acid and water, extracting the dye with chloroform filtering the solution through a short column of silica gel and concentrating the filtrate.  Similarly is prepared N,N1-(desamino-actinocyl)-bisaminoethanoic acid dimethyl ester, the dye after extraction being methylated with methyl iodide and silver oxide and adsorption on silica gel yielding two fractions, one comprising the ester and the other its 2-methyl ether; and N,N1 - (desamino - actinocyl) - bis - O - acetylthreonine and N,N1 - (desamino - actinocyl)-bis-threonine, the compounds being separated by adsorption on silica gel.  2 - Amino - 3 - hydroxy - 4 - methylbenzoic acid is prepared either by hydrolysis of its 3-methyl ether or reduction by sodium dithionite of the 2 - nitro compound; 2 - amino - 3 - hydroxy - 4-methylbenzoic acid methyl ester by treating the 2-nitro - 3 - hydroxy - 4 - methylbenzoic acid with methanolic hydrochloric acid solution to form 2-nitro - 3 - hydroxy - 4 methylbenzoic acid methyl ester and reducing this with sodium dithionite; N - (2 - amino - 3 - hydroxy - 4 - methylbenzoyl)-R (where R is an O-acetyl threonine, a glutathion, a p - amino - benzoyl - b  - alanyl - sarcosine ethyl ester, a p - amino - benzoyl - glycyl - sarcosine ethyl ester, a p-amino-benzoyl-glutamic acid diethyl ester, a d -amino-g -valerolactone, an ethylamine, a glycylvaline, a glycylvalineproline or a threonine residue) by treating 2-nitro-3 - hydroxy - 4 - methylbenzoic acid with sodium to form the sodium salt, reacting this with benzyl chloride to form 2-nitro-3-benzyloxy-4-methylbenzoic acid, converting the acid into its corresponding acid chloride and reacting this with the parent molecule of the residue R to form N-(2-nitro-3-benzyloxy-4-methylbenzoyl)-R, which is then catalytically hydrogenated; d  - amino - g  - valerolactone by reacting d -chloro-g -valerolactone with potassium phthalimide followed by acid hydrolysis; and N-(2-amino - 3 - hydroxy - 4 - methylbenzoyl) glycine from the corresponding 2-nitro ethyl ester by hydrolysis to form N-(2-nitro-3-hydroxy-4-methylbenzoyl) glycine which is then hydrogenated.