Triethylamine → (R)-N-(6-Methylisoquinolin-3-yl)-4H-1'-azaspiro[oxazole-5,3'-bicyclo[2.2.2]octan]-2-amine

Participants

Reaction Conditions

Reaction Steps

To (S)-3-(aminomethyl)quinuclidin-3-ol dihydrochloride (65.8 mg, 0.285 mmol) in N,N-dimethylformamide (6 mL) was added triethylamine (0.090 mL, 0.63 mmol) and 3-isothiocyanato-6-methylisoquinoline (57 mg, 0.285 mmol). The suspension was placed into a preheated oil-bath and stirred at 70° C. for 2 h and 30 min. N,N′-diisopropylcarbodiimide (0.177 mL, 1.14 mmol) was then added and the mixture was stirred at 85° C. for 16 h. The mixture was concentrated and purified by silica gel chromatography (0-40% [9:1 methanol:ammonium hydroxide] in chloroform) followed by purification by reverse phase preparatory HPLC (0-40% TFA-methanol-water). The solution of product was filtered through UCT Clean-up CHQAX15M25 cartridge with MeOH (3×10 ml) and concentrated to afford the expected product, (S)-1-((3-hydroxyquinuclidin-3-yl)methyl)-3-(6-methylisoquinolin-3-yl)thiourea, as a tan gum. 1H NMR (400 MHz, MeOD) δ ppm 9.11 (s, 1H), 8.02 (d, J=8.53 Hz, 1H), 7.80 (s, 1H), 7.74 (s, 1H), 7.47 (d, J=8.53 Hz, 1H), 4.47 (d, J=10.54 Hz, 1H), 4.31 (d, J=10.54 Hz, 1H), 4.10 (d, J=14.81 Hz, 1H), 3.92 (d, J=14.81 Hz, 1H), 3.53-3.71 (m, 2H), 3.27-3.51 (m, 3H), 2.84 (br.s, 1H), 2.55 (s, 3H), 2.48 (m, 1H), ) 2.10-2.30 (m, 3H). MS (LC/MS) R.T.=1.24; [M+H]+=323.2.

Provenance & Evidence