Pyrimidine, 2-(1-pyrrolidinyl)- (9CI)

Synthesis

The general procedure for the synthesis of 2-(pyrrolidin-1-yl)pyrimidine (HK-9) from tetrandrine and 2-chloropyrimidine was as follows: 9.53 mL (116 mmol) of tetrandrine (29) and 2.78 g (116 mmol) of sodium hydride (NaH) were added to 900 mL of anhydrous tetrahydrofuran (THF), and the mixture was refluxed for 0.5 hours. After cooling to room temperature, 12 g (105 mmol) of 2-chloropyrimidine (33) was slowly added dropwise and the reflux reaction was continued for 2 days. After completion of the reaction, the mixture was cooled in an ice bath. To the cooled reaction mixture was added 200 mL of water, followed by removal of THF under reduced pressure. the aqueous phase was extracted with chloroform (CHCl3), the organic phases were combined, washed with saturated brine, dried over anhydrous magnesium sulfate, and filtered. After removal of the solvent by concentration under reduced pressure, the residue was purified by column chromatography on silica gel with an eluent of 20:1 hexane/ethyl acetate (v/v). The purified product was recrystallized with ethyl ether (Et2O) to give 12.0 g (76% yield) of yellow solid HK-9 with a melting point of 39.0-39.6 °C. 1H NMR (CDCl3) δ 8.31 (d, J = 4.88 Hz, 2H), 6.45 (t, J = 4.88 Hz, 1H), 3.57 (t, J = 4.4 Hz, 4H), 2.01-1.98 (m, 4H). Elemental analysis (C8H11N3) Calculated values: C, 64.40; H, 7.43; N, 28.16. Measured values: C, 64.42; H, 7.53; N, 27.97.

References

[1] Turkish Journal of Chemistry, 2015, vol. 39, # 1, p. 121 - 129
[2] European Journal of Organic Chemistry, 2016, vol. 2016, # 36, p. 5957 - 5963
[3] Tetrahedron Letters, 2004, vol. 45, # 4, p. 757 - 759
[4] ChemSusChem, 2013, vol. 6, # 8, p. 1455 - 1460
[5] Patent: US2014/235858, 2014, A1. Location in patent: Paragraph 0077