Diphosgene → 1-(4-(1-(2-aminopyridin-4-yl)ethoxy)naphthalen-1-yl)-3-(3-tert-butyl-1-p-tolyl-1H-pyrazol-5-yl)urea

Participants

Reaction Conditions

Reaction Steps

To a solution of 3-tert-butyl-1-p-tolyl-1H-pyrazol-5-amine (4) (WO 2000043384) (57 mg, 0.250 mmol) in DCM (6.0 mL) was added a saturated aq NaHCO3 solution (4.0 mL), and the mixture was stirred vigorously. The mixture was cooled to 0° C. and then trichloromethylchloroformate (0.091 ml, 0.750 mmol) was added in one portion. The resulting mixture was stirred at 0° C. for 1.5 hr. The layers were separated, the organic extract was dried and the solvents removed under reduced pressure to afford an oil, which was left drying under high vacuum, at 35° C. for a further 35 min. The resulting oil was taken up into THF (5.0 mL), and then added to 4-(1-(4-aminonaphthalen-1-yloxy)ethyl)pyridin-2-amine (24) (81 mg, 0.290 mmol). DIPEA (179 μl, 1.029 mmol) was added, and the reaction mixture was stirred at RT for 16 hr. Water (15 mL) and EtOAc (10 mL) were added to the reaction mixture and the layers were separated. The aqueous layer was extracted with EtOAc (15 mL). The combined organic extracts were washed with brine (20 mL), dried and the solvents removed under reduced pressure. The resulting residue was dissolved in MeOH (5.0 mL) and AcOH (2.0 mL) and subjected to SCX capture and release. The crude mixture was purified by column chromatography (12 g), eluting with 0 to 10% MeOH in DCM, to give 1-(4-(1-(2-aminopyridin-4-yl)ethoxy)naphthalen-1-yl)-3-(3-tert-butyl-1-p-tolyl-1H-pyrazol-5-yl)urea (Intermediate F) (63 mg, 38%) as a beige powder: m/z 535 (M+H)+ (ES+).

Provenance & Evidence