7-bromopyrrolo[1,2-f][1,2,4]triazin-4-amine

Uses

7-bromopyrrolo[2,1-f][1,2,4]triazin-4-amine is used in preparation of N-Heterocyclic compounds for pharmaceutical use including as anticancer agents and PRMT5 inhibitors.

Synthesis

The general procedure for the synthesis of 4-amino-7-bromopyrrolo[2,1-f][1,2,4]triazines from 4-amino pyrrolo[2,1-f][1,2,4]triazines is as follows: a solution of anhydrous DMF (200 mL) containing 4-amino pyrrolo[2,1-f][1,2,4]triazines (21.0 g, 0.157 mol) was stirred and cooled to -20 °C, followed by the batch addition of 1,3-dibromo-5,5-dimethylglycolide (22.4 g, 0.078 mol), the addition process lasted 45 min. After completion of addition, stirring of the reaction mixture was continued for 45 min and the progress of the reaction was monitored by TLC (silica gel plate, GHLF, 5% CH3OH/CH2Cl2). Upon completion of the reaction, the reaction was quenched by the addition of saturated Na2SO3 solution (300 mL), the resulting suspension was stirred, and the solid product was collected by filtration. The filter cake was washed with water and dried by diafiltration. Subsequently, the dried solid was partitioned between ethyl acetate (1 L) and 5% sodium carbonate solution (1 L) to separate the organic and aqueous layers. The organic layer was washed with fresh 5% sodium carbonate solution and dried with magnesium sulfate. All organic phases were combined and filtered through a Magnesol pad and the filtrate was concentrated under vacuum to give the crude product 4-amino-7-bromopyrrolo[2,1-f][1,2,4]triazine (29.9 g, 90% yield). 21.5 g of the crude product was recrystallized in hot ethyl acetate (300 mL, 70 °C) to give a colorless solid (12.3 g) with about 2% of dibrominated byproducts. The structure of the product was confirmed by 1H-NMR (CD3OD) and mass spectrometry (LC/MS, +ESI): 1H-NMR δ 7.84 (s, 1H), 6.95 (d, 1H, J = 4.7 Hz), 6.71 (d, 1H, J = 4.7 Hz), 4.89 (s, 3H, -NH2 + H2O); MS m/z = 213.1 [M+H].

References

[1] Patent: WO2007/56170, 2007, A2. Location in patent: Page/Page column 74-75
[2] Patent: WO2007/64931, 2007, A2. Location in patent: Page/Page column 164
[3] Asian Journal of Chemistry, 2014, vol. 26, # 20, p. 7083 - 7084
[4] ACS Medicinal Chemistry Letters, 2017, vol. 8, # 1, p. 133 - 137