2-Amino-4-chloropyrimidine-an pharmaceutical intermediate

Fig 1. Chemical structure formula of 2-amino-4-chloropyrimidine

2-Amino-4-chloropyrimidine (C4H4ClN3, CAS registry No. 3993-78-0) is a white solid. Its melting point is 155-160 oC and flash point is 144.1 oC.

The electrolytic reduction of 2-amino-4-chloropyrimidine has been studied with lead or mercury cathodes in ammoniacal medium[1]. 2-Amino-4-chloropyrimidine can give two polarographic waves in the pH region of 7.4-8.9. Macroscale electrolysis at lead or mercury cathodes in ammoniacal medium shows that the first wave of the chlorocompounds arises from reductive dehalogenation. The second wave of the chlorocompounds coincides with the single wave of their parent compounds, the 2-aminopyrimidines, and is ascribed to reduction of the pyrimidine nucleus in both cases. The mechanism of reduction is tentatively identified as pure electrolytic reduction.

2-Amino-4-chloropyrimidine and its derivatives can be used as intermediates in pharmaceutical synthesis. For example, 2-amino-4-chloropyrimidine and its derivatives can be used for the synthesis of 6-[2-(phosphonomethoxy)alkoxy]pyrimidines, which have antiviral activity[2]. Another example is using 2-amino-4-chloropyrimidine as substrate for the synthesis of a new series of pyrimidine compounds, which can be used as glucagon-like peptide-1 receptor agonists[3]. These substituted pyrimidine analogs were synthesized using an economical and environmentally friendly procedure. The anti-diabetes activities of the newly synthesized compounds were evaluated in cultured cells. 2-Amino-4-chloropyrimidine can also be used for the preparation of the key intermediates for the synthesis of Imatinib (Gleevec/GlivecTM; STI571), which is known as an inhibitor of tyrosine kinases and is used for the chemotherapy of chronic myeloid leukemia and gastrointestinal stromal tumors[4].

2-Amino-4-chloropyrimidine can be prepared from 2,4-dichloropyrimidine, which reacted with ammonia[5]. However, the regioisomers of 2-amino-4-chloropyrimidine, 2-chloro-4-aminopyrimidine, was also produced. Unfortunately, this technique gave 2-amino-4-chloropyrimidine as the minor product. Another approach, more suitable to large scale preparation of 2-amino-4-chloropyrimidine required a multi-step synthetic strategy[6]. Starting from thiouracil, 2-methylthio-3H-pyrimidine-4-one was easily produced by methylation with CH3I, a reaction that occurs very quickly with precipitation of the product in quantitative yield. Then 2-methylthio-3H-pyrimidine-4-one was converted to isocytosine, a commercially available but quite expensive regioisomer of the natural nucleoside cytosine by reaction in a melted mixture with ammonium acetate at 160 oC. The final procedure required reaction between isocytosine and POCl3 at reflux for 3 h and, after work-up, 2-amino-4-chloropyrimidinewas isolated in a good yield.

References

[1]Sugino, K.; Shirai, K.; Sekine, T.; Odo, K., Electrolytic Reduction of 2-Amino-4-Chloropyrimidine, 2-Amino-4-Chloro-6-Methylpyrimidine, and 2-Aminopyrimidine. Journal of the Electrochemical Society 1957, 104 (11), 667-672.
[2]Holý, A.; Votruba, I.; Masojídková, M.; Andrei, G.; Snoeck, R.; Naesens, L.; De Clercq, E.; Balzarini, J., 6-[2-(Phosphonomethoxy)alkoxy]pyrimidines with Antiviral Activity. Journal of Medicinal Chemistry 2002, 45 (9), 1918-1929.
[3]AlNeyadi, S. S.; Adem, A.; Amer, N.; Salem, A. A.; Abdou, I. M., Synthesis and in vitro biological evaluation of new pyrimidines as glucagon-like peptide-1 receptor agonists. Bioorganic & medicinal chemistry letters 2017, 27 (22), 5071-5075.
[4]Heo, Y.; Hyun, D.; Kumar, M. R.; Jung, H. M.; Lee, S., Preparation of copper(II) oxide bound on polystyrene beads and its application in the aryl aminations: synthesis of Imatinib. Tetrahedron Letters 2012, 53 (49), 6657-6661.
[5]https://pubchem.ncbi.nlm.nih.gov/compound/223332
[6]http://www.chemspider.com/Chemical-Structure.193961.html?rid=bb21925c-dc1b-452c-a8dc-6dba4a80ee14

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