2,4,6-Triaminopyrimidine

2,4,6-Triaminopyrimidine
Names
Preferred IUPAC name
Pyrimidine-2,4,6-triamine
Identifiers
3D model (JSmol)
ChEBI
ChEMBL
ChemSpider
ECHA InfoCard 100.012.473
EC Number
  • 213-720-7
405732
UNII
  • InChI=1S/C4H7N5/c5-2-1-3(6)9-4(7)8-2/h1H,(H6,5,6,7,8,9)
    Key: JTTIOYHBNXDJOD-UHFFFAOYSA-N
  • C1=C(N=C(N=C1N)N)N
Properties
C4H7N5
Molar mass 125,13 g·mol−1
Except where otherwise noted, data are given for materials in their standard state (at 25 °C [77 °F], 100 kPa).
Infobox references

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.[1] 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.[2]

Synthesis of 2,4,6-triaminopyrimidine
Synthesis of 2,4,6-triaminopyrimidine

The product can be isolated from the solution as a well-crystallizing sulfate.[2] When a more manageable guanidine salt is used, e.g. guanidine hydrochloride, the base sodium methanolate is added to liberate free guanidine.[3] 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.[4]

Properties

Pure 2,4,6-triaminopyrimidine is a white crystalline solid "which precipitates in long needles when recrystallized from hot, dilute alcohol".[2] 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).[5]

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).[6][7]

Conjugate of 2,4,6-triaminopyrimidine and ribose
Conjugate of 2,4,6-triaminopyrimidine and ribose

Reaction of 2,4,6-triaminopyrimidine with the sodium salt of nitromalonaldehyde[8] (prepared from mucobromic acid[9] 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.[10][11]

DHFR inhibitor from TAP
DHFR inhibitor from TAP

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,[2] sodium dithionite (Na2S2O4),[12] zinc dust/hydrochloric acid,[13] or more effectively by catalytic hydrogenation over palladium to yield 2,4,5,6-tetraaminopyrimidine[14] in das u. a. als Entwickler für oxidative Haarfarben[3][15] (II).

Synthesis of 2,4,5,6-tetraaminopyrimidine from TAP
Synthesis of 2,4,5,6-tetraaminopyrimidine from TAP

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.[3]

In an early synthetic route for the potassium-sparing diuretic triamterene, 5-nitroso-2,4,6-triaminopyrimidine (I) is cyclized with phenylacetonitrile[16] in the presence of sodium methanolate to yield the final product.

Synthesis of triamterene from TAP (last step)
Synthesis of triamterene from TAP (last step)

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.

Folic acid and antagonists derived from TAP
Folic acid and antagonists derived from TAP

References

  1. ↑ Menor Salván, C.; Bouza, Marcos; Fialho, David M.; Burcar, Bradley T.; Fernández, Facundo M.; Hud, Nicholas V. (2020). "Prebiotic Origin of Pre-RNA Building Blocks in a Urea 'Warm Little Pond' Scenario". ChemBioChem. 21 (24): 3504–3510. doi:10.1002/cbic.202000510. PMID 32770593.
  2. 1 2 3 4 W. Traube (1904), "Über (2)-Amino-Adenin (2.6-Diaminopurin)", Chem. Ber., vol. 37, no. 4, pp. 4544–4547, doi:10.1002/cber.19040370454
  3. 1 2 3 US 4145548, D. Rose, "Method for the production of 5-nitroso-2,4,6-triaminopyrimidine", published 1979-3-20, assigned to Henkel KGaA
  4. ↑ E.P. Aparna, K.S. Devaky (2018), "Microwave assisted solid phase synthesis of trisubstituted pyrimidines", J. Chem. Pharm. Res., vol. 10, no. 8, pp. 67–72
  5. ↑ Datenblatt 2,4,6-Triaminopyrimidin, 97 % bei Fisher Scientific, retrieved 28 November 2022. (PDF).
  6. ↑ Chen, Michael C.; Cafferty, Brian J.; Mamajanov, Irena; Gállego, Isaac; Khanam, Jaheda; Krishnamurthy, Ramanarayanan; Hud, Nicholas V. (2013). "Spontaneous prebiotic formation of a β-ribofuranoside that self-assembles with a complementary heterocycle". J. Amer. Chem. Soc. 136 (15): 5640–5646. doi:10.1021/ja410124v.
  7. ↑ Kaur, Sarabjeet; Sharma, Purshotam; Wetmore, Stacey D. (2019). "Can Cyanuric Acid and 2,4,6-Triaminopyrimidine Containing Ribonucleosides be Components of Prebiotic RNA? Insights from QM Calculations and MD Simulations". ChemPhysChem. 20 (11): 1425–1436. doi:10.1002/cphc.201900237. PMID 30997731.
  8. ↑ Externe 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.
  9. ↑ Paul 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).
  10. ↑ Gangjee, Aleem; Vasudevan, Anil; Queener, Sherry F.; Kisliuk, Roy L. (1996). "2,4-Diamino-5-deaza-6-substituted pyrido[2,3-d]pyrimidine antifolates as potent and selective nonclassical inhibitors of dihydrofolate reductases". J. Med. Chem. 39 (7): 1438–1446. doi:10.1021/jm950786p. PMID 8691474.
  11. ↑ Gangjee, Aleem; Adair, Ona O.; Pagley, Michelle; Queener, Sherry F. (2008). "N9-Substituted 2,4-Diaminoquinazolines: Synthesis and Biological Evaluation of Lipophilic Inhibitors of Pneumocystis carinii and Toxoplasma gondii Dihydrofolate Reductase". J. Med. Chem. 51 (19): 6195–6200. doi:10.1021/jm800694g. PMC 3885247. PMID 18771252.
  12. ↑ US 4167633, T.J. Morrow, "Preparation of 2,4,5,6-tetraaminopyrimidine from 2,4,6-triaminopyrimidine", published 1979-9-11, assigned to The United States of America as represented by the Department of Health, Education and Welfare
  13. ↑ US 4247693, P.F. O'Brien, J. Kazan, J.R. Andrade, "Process for the preparation of 2,4,5,6-tetraaminopyrimidine sulfate", published 1981-1-27, assigned to American Cyanamide Co.
  14. ↑ WO 9721711, M. Eyer, W. Pfleiderer, S. Taghavi-Moghadam, "Process preparing 4-aminopteridine derivatives", published 1997-06-19, assigned to Lonza AG
  15. ↑ Externe 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.
  16. ↑ US 3081230, J. Weinstock, V.D. Wiebelhaus, "Diuretic and antihypertensive triaminoarylpteridines", published 1963-3-12, assigned to Smith Kline & French Laboratories
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