Pyrimidine Series Research Articles

Simple pyrimidines. XI. 5-Nitropyrimidine.

5-Nitropyrimidine has been made by oxidizing its 4,6-dihydrazino-derivative with silver oxide. 2-Methyl- and 2-benzyl-5-nitropyrimidine, made similarly, differ from compounds previously so formulated. The structures of the nitropyrimidines have been confirmed by chemical and spectral means. Their cations in water exist as covalent hydrates, the first such adducts observed in the pyrimidine series.

Substituted uracil herbicides.

Explorations in the pyrimidine series have led to the discovery of highly active herbicides, of which 3-butyl-6-methyluracil and 5-bromo-3-isopropyl-6-methyluracil are examples.

Potential Antimetabolites. I. Selective Thiation of Uracil and 1, 2, 4-Triazine-3, 5 (2<I>H</I>, 4<I>H</I>)-dione (6-Azauracil)

1, 2, 4-Triazine-3, 5 (2H, 4H)-dione (6-azauracil)(I; R =H) and uracil were partially thiated to afford 5-mercapto-1, 2, 4-triazin-3 (2H)-one (II; R H) and 4-mercapto-2 (1H)-pyrimidinone, respectively, in good yields by the use of limited amount of phosphorus pentasulfide. These are the first examples of the success of monothiation in triazine and pyrimidine series. The alkylation of 5-mercapto-1, 2, 4-triazin-3 (2H)-one gave the corresponding alkylthio derivatives (IV and V; R=H) from which 5-amino-1, 2, 4-triazin-3 (2H)-one (6-azacytosine)(III; R=H) was synthesized in an excellent yield.

Apparent Migration of N-Methyl Groups in the Pyrimidine Series

THE long-standing problem of how methyl groups migrate from nuclear to extra-nuclear nitrogen atoms in heterocyclic compounds has now been decided experimentally in the pyrimidine series.

Improved syntheses in the pyrimidine series. VI. 4‐amino‐3‐methyl‐5‐nitro‐2‐pyrimidone and some of its purine and pteridine derivatives

AbstractA direct route from nitroacetonitrile to 3‐methyl‐5‐nitrocytosine (II; R=NO2) is described. This led to the preparation of the long‐sought 5‐amino‐3‐methylcytosine and the purines and pteridines derivable from it. The structure of the nitro compound was rigorously confirmed by comparison with other isomers and by conversion (after reduction of the nitro group) into 1‐methy1–2‐pteridone, its 6:7‐dimethyl derivative, and into 8‐hydroxy‐3‐methyl‐2‐purinone. Isomers corresponding to these were prepared independently for comparison. Attempted conversion with carbon disulphide and pyridine, into 8‐mercapto‐3‐methyl‐2‐purinone however gave a rearranged product, shown to be 2‐hydroxy‐8‐mercapto‐9‐methylpurine by unambiguous synthesis. Ultra‐violet spectra and ionisation constants are tabulated.

STUDIES OF THE MECHANISM OF ACTION OF URETHANE IN INITIATING PULMONARY ADENOMAS IN MICE

The process of carcinogenesis following exposure of mice to urethane is demonstrated in the present work to be intimately related to nucleic acid synthesis. Injection of animals with a DNA hydrolysate immediately prior to a single exposure of the animals to urethane markedly reduced the number of pulmonary adenomas initiated. Aminopterin, known to interfere in nucleic acid synthesis (46), potentiated the carcinogenic action of urethane and this potentiation was blocked by injection of a DNA hydrolysate. Of the components and precursors of nucleic acids the pyrimidine series seemed especially concerned. Alterations in the utilization of oxaloacetate, ureidosuccinic acid, dihydro-orotic acid, orotic acid, cytidylic acid, and thymine appeared to be critical steps in the oncogenic process, following upon the primary disorder of cellular metabolism initiated by the carcinogen. All these substances except oxaloacetate profoundly reduced the number of tumors initiated by urethane. Oxaloacetate potentiated the carcinogenic effect. When these results are viewed together and in relation to known facts concerning nucleic acid synthesis they provide evidence suggesting that the point of action of the carcinogen is in the pathway of nucleic acid synthesis below orotic acid and perhaps at the level of ureidosuccinic acid. The potentiating influence of adenine, 4-amino-5-imidazole carboxamide, and aminopterin, the lack of effect of uracil, and the inhibitory influence of thymine together suggest that DNA rather than RNA is the nucleic acid critical to the oncogenic response of mice to urethane.

Improved syntheses in the pyrimidine series. V. some derivatives of 4‐methylaminopyrimidine

AbstractThe preparation of several derivatives of 4‐methylaminopyrimidine is described. When 2‐chloro‐4‐methylamino‐5‐nitropyrimidine is treated with aqueous sodium hydrogen sulphide, not only is the expected 5‐amino‐2‐mercapto‐4‐methylaminopyrimidine formed but also 5‐amino‐2: 6‐dimercapto‐4‐methylaminopyrimidine. Improved ways of making 5‐aminocytosine (4: 5‐diamino‐2‐hydrpxypyrimidine) and 2: 4: 5‐triaminopyrimidine, viz. by catalytic reduction of the corresponding 5‐nitro compounds, are reported.

Improved syntheses in the pyrimidine series. IV. N‐methyl derivatives of 4: 5‐diaminopyrimidine

Abstract4‐Amino‐5‐methylaminopyrimidine has been synthesized by reduction with lithium aluminium hydride of the formyl group in 4‐amino‐5‐formamido‐2‐methylthiopyrimidine followed by removal of the 2‐substituent. A route to 5‐amino‐4‐hydroxy‐6‐methylaminopyrimidine is described. The Whitehead synthesis has been extended to the use of cyanoacetic acid as a reactant. Decarboxylation of the resulting 4‐amino‐5‐carboxy‐3‐methyl‐2‐pyrimidone, however, gave unexpectedly 2‐hydroxy‐4‐methylaminopyrimidine. Several improvements in the preparation of known related (methylated) compounds, including the first isolation of 5‐amino‐1‐methyl‐4‐methylamino‐2‐pyrimidone are described.

Improved syntheses in the pyrimidine series. III. 5‐amino‐4‐methylaminopyrimidine

AbstractA synthesis of 5‐amino‐4‐methylaminopyrimidine is reported, which involves the successful monoamination of 5‐amino‐4: 6‐dichloropyrimidine with methylamine. It is shown, however, that similar monoaminations of 2: 4‐ and 4: 6‐dichloro‐5‐nitropyrimidine (which are possible with ammonia) with methylamine lead only to bismethylamino‐5‐nitropyrimidines. Amination of 2: 4‐dimercapto‐5‐nitropyrimidine with methylamine also gives the diaminated product, but when 2: 4‐dimercapto‐5‐aminopyrimidine is used no reaction takes place.

Improved syntheses in the pyrimidine series. II. The preparation of 4:5‐diaminopyrimidine

AbstractA greatly improved method of preparation of 4:5‐diaminopyrimidine, which is an important starting material for pteridine and purine syntheses, is described in detail. The route from thiouracil involves eight stages, but purifications, except that of the final product, have been avoided.

Improved syntheses in the pyrimidine series. 1. The use of pyrimidine‐thiols

AbstractSyntheses suitable for large laboratory‐scale working, are described for thiocytosine, cytosine, 4‐hydroxypyrimidinc, 4‐amino‐pyrimidine, 2 : 4‐ and 4: 6‐diaminopyrimidincs, uracil, 4‐amino‐6‐hydroxypyrunidine and several of their derivatives. The majority of these syntheses start from thiouracil, which has recently become plentiful; all involve replacement of a thiol‐group by −NH2, ‐OH or‐H.