Sodium hydride → 2-(4-((1R,2S)-2-(2-(5-(1H-1,2,3-triazol-1-yl)pyridin-2-yloxy)ethyl)cyclopropyl)piperidin-1-yl)-5-chloropyrimidine

Participants

Reaction Conditions

Reaction Steps

A suspension of NaH (720 mg; 60 wt %; 432 mg NaH contained; 17.99 mmol) in DMF (9 mL) at 0° C. was treated with a solution of 2-{(1S,2R)-2-[1-(5-chloropyrimidin-2-yl)piperidin-4-yl]cyclopropyl}ethanol (3.9 g; 13.84 mmol) in DMF (9 mL). The mixture was stirred at 0° C. for 30 minutes. The mixture was treated with a solution of 2-fluoro-5-(1H-1,2,3-triazol-1-yl)pyridine (2.499 g; 15.22 mmol) in DMF (10 mL). The reaction was stirred at 0° C. for 45 minutes, then allowed to warm to room temperature and stirred overnight. The reaction was quenched with saturated aqueous NH4Cl and the mixture partitioned between ethyl acetate and water. The organic layer was washed twice more with water, dried over sodium sulfate, filtered and evaporated to a residue. The residue was chromatographed (Horizon 65i silica cartridge; 30% to 45% ethyl acetate/heptane). The fractions containing the desired product were combined and evaporated to a white solid. Crystalline solid was also recovered from the chromatography fractions. The solid isolated from chromatography was recrystallized from EtOH/heptane. The solid (4 g) was suspended in EtOH (150 ml), then heated until completely dissolved, allowed to cool to RT and heptane (100 ml) was added. The mixture was aged at RT overnight, cooled to 0° C. for 5 minutes and filtered to provide the title compound). LCMS: calc. 425.17 obs: 426.09 (M+1). 1H NMR (CDCl3): δ 8.48 (d, 1H), 8.20 (s, 2H), 7.97 (dd, 1H), 7.93 (s, 1H), 7.87 (s, 1H), 7.26 (s, CDCl3), 6.89 (d, 1H), 4.47 (br t, 2H), 4.47 (t, 2H), 2.87 (m, 2H), 2.15 (m, 1H), 1.86 (br t, 2H), 1.58 (m, 1H), 1.57 (S, H2O), 1.37 (m, 2H), 1.12 (m, 1H), 0.94 (m, 1H), 0.70 (m, 1H), 0.61 (m, 1H), −0.08 (q, 1H).

Provenance & Evidence