2,4,6-Triaminopyrimidine is a pyrimidine (1,3-diazine) carrying three symmetrically arranged amino groups and has been proposed as a potential prebiotic nucleic base analog. Pyrimidine triamine serves as a starting material for the production of hair dyes and explosives, but most notably for the vitamin folic acid and for pharmaceuticals such as malaria treatments, the cytostatic agents aminopterin and methotrexate, as well as the diuretic triamterene.
Occurrence and preparation In 1905, Wilhelm Traube reported the synthesis of 2,4,6-triaminopyrimidine from malonic acid dinitrile and guanidine in the presence of sodium methanolate using ethanol as solvent.
The product can be isolated from the solution as a well-crystallizing sulfate. When a more manageable guanidine salt is used, e.g. guanidine hydrochloride, the base sodium methanolate is added to liberate free guanidine. Because the aromatic triamine is highly sensitive to oxidation, all operations must be carried out under exclusion of air.
The synthesis of TAP using guanidine bound to polystyrene according to the principle of a Merrifield synthesis, with malodinitrile and subsequent cleavage using trifluoroacetic acid under microwave chemistry conditions, has also been reported to yield very high product quantities (92%) within short reaction times.
Properties Pure 2,4,6-triaminopyrimidine is a white crystalline solid "which precipitates in long needles when recrystallized from hot, dilute alcohol". The substance rapidly forms dark brown oxidation products upon exposure to air. TAP is highly soluble in water (36.5 g/kg at 20 °C) and in methanol (22.7 g/kg at 20 °C), but less soluble in ethanol (4.5 g/kg at 20 °C).Datenblatt 2,4,6-Triaminopyrimidin, 97 % bei Fisher Scientific, retrieved 28 November 2022. (PDF).
Applications The spontaneous reaction of 2,4,6-triaminopyrimidine with ribose under simulated conditions of chemical evolution forms a nucleoside TAP–ribose conjugate that associates with complementary cyanuric acid. This reaction serves as a model for the prebiotic formation of ribonucleic acid (pre-RNA).
Reaction of 2,4,6-triaminopyrimidine with the sodium salt of nitromalonaldehydeExterne Identifikatoren von bzw. Datenbank-Links zu Nitromalondialdehyde monohydrate (Name im Wikidata-Eintrag abweichend, dort: Sodium nitromalonaldehyde): CAS-Nr.: 34461-00-2, EG-Nr.: 636-459-4, ECHA-InfoCard: 100.164.255, PubChem: 2786779 (Wert fehlt im Wikidata-Eintrag), ChemSpider: 21169750 (Wert fehlt im Wikidata-Eintrag), Wikidata: Q72508036. (prepared from mucobromic acidPaul E. Fanta: 2,4,6-Triaminopyrimidin In: Organic Syntheses. 32, 1952, S. 95, doi:10.15227/orgsyn.032.0095; Coll. Vol. 4, 1963, S. 844 (PDF). and nitrous acid) yields a heteroaromatic compound (A), which is subsequently converted in two steps into an inhibitor of dihydrofolate reductase active against Pneumocystis carinii and Toxoplasma gondii.
Treatment of 2,4,6-triaminopyrimidine with nitrous acid (HNO2) affords the 5-nitroso compound (I), which can be further reduced using ammonium sulfide (NH4)2S, sodium dithionite (Na2S2O4), zinc dust/hydrochloric acid, or more effectively by catalytic hydrogenation over palladium to yield 2,4,5,6-tetraaminopyrimidine in das u. a. als Entwickler für oxidative HaarfarbenExterne Identifikatoren von bzw. Datenbank-Links zu 2,4,5,6-Tetraaminopyrimidin Name im Wikidata-Eintrag abweichend, dort: 2,4,5,6-tetraaminopyrimidine): CAS-Nr.: 1004-74-6, EG-Nr.: 213-724-9, ECHA-InfoCard: 100.012.477 PubChem: 70487, ChemSpider: 63662, Wikidata: Q15726087. (II).
5-Nitroso-2,4,6-triaminopyrimidine (I) can also be obtained directly in a one-pot reaction from the starting materials used for TAP without intermediate isolation, providing very good yields.
In an early synthetic route for the potassium-sparing diuretic triamterene, 5-nitroso-2,4,6-triaminopyrimidine (I) is cyclized with phenylacetonitrile in the presence of sodium methanolate to yield the final product.
The extensive work conducted between 1970 and 2000 on the synthesis of 2,4,5,6-tetraaminopyrimidine from 2,4,6-triaminopyrimidine was driven by the high demand for this tetramine as a precursor for triamterene and particularly for the vitamin folic acid and its antagonists used in cancer therapy, such as aminopterin and especially methotrexate.
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