5-iodo-A^-((lr,4r)-4-methylcyclohexyl)pyridine-2,4- diamine. N4-((lr,4r)-4-Methylcyclohexyl)pyridine-2,4-diamine
STEP A
4-Chloropyrimidine-2-amine (commercially available from Sigma-Aldrich, St. Louis, MO) (1000 g, 7.72 mol, 1.0 eq), trans- 4-methylcyclohexylamine hydrochloride (commercially available from TCI America, M1780) (1500 g, 10.03 mol, 1.3 eq) and TEA (3.23 L, 23.2 mol, 3.0 eq) were mixed together in n-butanol (8 L). The reaction mixture was heated at reflux for 36 hours and monitored using LCMS. Upon completion, the reaction mixture was cooled to room temperature, diluted with water (8 L) and extracted with EtOAc (2 x 10 L). The organic layers were combined, dried over Na2S04, and concentrated under reduced pressure to give the title compound (1770 g) which was us
STEP B
Synthesis of 5-iodo-A^-((lr,4r)-4-methylcyclohexyl)pyridine-2,4- diamine. N4-((lr,4r)-4-Methylcyclohexyl)pyridine-2,4-diamine (1770 g, 8.58 mol, 1.0 eq) was dissolved in anhydrous DMF (8 L). To this solution under N2 atmosphere at 10 °C was added NIS (1.93 kg, 8.58 mol, 1.0 eq) in portions over 10 minutes. Upon completion of the addition, the reaction mixture was stirred at room temperature for 2 hours. The reaction was monitored using LCMS. Upon completion, the reaction mixture was cooled using an ice bath, quenched with saturated aqueous sodium carbonate (5 L) and extracted with EtOAc (2 x 15 L). The combined organic extracts were washed with saturated aqueous sodium carbonate (2 x 5 L), water (3 x 2 L), dried over Na2S04, and concentrated under reduced pressure. The residue was purified using column chromatography eluting with 25% to 40% EtOAc in hexanes to provide the title compound (1.47 kg, 57% over two steps).
^-NMR (300 MHz, DMSO-d6)
δ ppm 0.85 (3H, d, J= 7.2 Hz),
0.98 (1H, dd, J= 12.9, 2.7 Hz),
1.41 – 1.27 (3H, m),
1.66 (2H, d, J = 12.3 Hz),
1.78 (2H, d, J= 12.3 Hz),
3.85 (1H, m),
5.48 (1H, d, J= 8.1 Hz),
6.16 (2H, br s),
7.86 (1H, S)
MS 333 M+1
MS 333 M+1
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