Triethylamine → (R)-N-(5-chloro-4-methylpyridin-2-yl)-4H-1'-azaspiro[oxazole-5,3'-bicyclo[2.2.2]octan]-2-amine

Participants

Reaction Conditions

Reaction Steps

To 5-chloro-2-isothiocyanato-4-methylpyridine (0.37 g, 2.0 mmol) in N,N-dimethylformamide (20 mL) was added triethylamine (0.7 mL, 5.0 mmol) and (S)-3-(aminomethyl)quinuclidin-3-ol dihydrochloride (from Step B of Example 17) (0.47 g, 2.0 mmol) at room temperature. The reaction was stirred at 70° C. for 2 hours. The reaction was cooled to room temperature and concentrated in vacuo. The crude urea was purified by chromatography (Biotage: 85% CHCl3, 14% MeOH, 1% NH4OH). The product was then treated with N,N-dimethylformamide (20 mL) and N,N′-diisopropylcarbodiimide (0.94 mL, 6.0 mmol). The reaction was heated to 70° C. for 2 hours. The reaction was cooled to room temperature and concentrated to yield the crude product. The crude product was purified by chromatography (Biotage: 85% CHCl3, 14% MeOH, 1% NH4OH) to yield (R)—N-(5-chloro-4-methylpyridin-2-yl)-4H-1′-azaspiro[oxazole-5,3′-bicyclo[2.2.2]octan]-2-amine (0.19 g, 0.61 mmol, 30.3% yield) as a white powder. 1H NMR (500 MHz, DMSO-D6) δ ppm 8.79 (s, 1 H), 8.08-8.15 (m, 2 H), 6.78 (s, 1 H), 3.82 (d, J=8.55 Hz, 2 H), 3.55 (d, J=10.38 Hz, 2 H), 2.93-3.02 (m, 5 H), 2.71-2.80 (m, 5 H), 2.66 (t, J=7.63 Hz, 4 H), 2.23-2.29 (m, 7 H), 1.94-2.02 (m, 2 H), 1.92 (s, 1 H), 1.86 (s, 2 H), 1.53-1.62 (m, 5 H), 1.41-1.49 (m, J=12.55, 9.88, 7.02, 2.29 Hz, 2 H). MS (LC/MS) R.T.=0.72; [M+H]+=307.1.

Provenance & Evidence