Pteridine studies. Part XLI. New routes to 4-aminopteridines via 3-(dimethylaminomethyleneamino)pyrazine-2-carbonitrile and related compounds

Abstract

3-Aminopyrazine-2-carboxamide was converted into 3-(dimethylaminomethyleneamino)pyrazine-2-carbonitrile (1b) with dimethylformamide and phosphoryl chloride. This amidine (1b) was produced by the same reagents also from 3-aminopyrazine-2-carbonitrile (1a), and by the action of dimethylamine on 3-ethoxymethyleneamino-pyrazine-2-carbonitrile (1c). Compound (1c) was made from 3-aminopyrazine-2-carbonitrile with triethyl orthoformate and acetic anhydride.

Compounds (1a—c) were used in several new pteridine syntheses. The amidine (1b) gave 4-amino- and 4-methyl-amino-pteridine (2a and b) with ammonium and methylammonium acetate, respectively. Use of the 6-chloro-derivative of amidine (1b) similarly led to 6-chloro-4-amino- and -4-methylamino-pteridine. Pteridine-4-thione was obtained from the amidine (1b) and sodium hydrosulphide. The ethoxymethylene compound (1c) gave 4-aminopteridine with ammonia but 3,4-dihydro-4-imino-3-methylpteridine (3) with cold methylamine; this imine was easily isomerized to 4-methylaminopteridine by a Dimroth reaction, but proved stable as a solid. 3-Aminopyrazine-2-carbonitrile (1a) gave 4-aminopteridine with formamidine acetate at 140°.

Some unusual pyrazine reactions were encountered. The ethoxymethylene compound (1c), after brief contact with ammonium acetate solution, gave 3-(aminomethyleneamino)pyrazine-2-carbonitrile (1e). The ethoxy-methylene compound (1c) was hydrolysed by the water in cold 95% ethanol to 3-formamidopyrazine-2-carbonitrile (1d), and condensed with hydrazine hydrate to give 3-hydrazinomethyleneaminopyrazine-2-carboxamidrazone (4b). 3-Aminopyrazine-2-carbonitrile (1a) similarly gave 3-aminopyrazine-2-carboxamidrazone (4a). 3-Aminopyrazine-2-carboxamide was quantitatively brominated to give 3-amino-6-bromopyrazine-2-carboxamide.