Cesium carbonate → (R)-N-(6-bromothiazolo[5,4-b]pyrazin-2-yl)-4H-1'-azaspiro[oxazole-5,3'-bicyclo[2.2.2]octan]-2-amine

Participants

Reaction Conditions

Reaction Steps

A mixture of dimethyl 6-bromothiazolo[5,4-b]pyrazin-2-ylcarbonimidodithioate (300 mg, 0.895 mmol), (S)-3-(aminomethyl)quinuclidin-3-ol dihydrochloride (210 mg, 0.895 mmol) and cesium carbonate (600 mg, 1.79 mmol) in acetonitrile (25 mL) was heated on a 100° C. oil bath for 2 hours in an open flask, with nitrogen bubbling through the solution the entire time to help in the removal of methanethiol. After 2 hours, TLC showed the reaction to be complete, so the mixture was cooled to ambient temperature, diluted with water and concentrated in vacuo. The mixture was extracted with chloroform (4×). The combined organics were washed with brine, dried over sodium sulfate, filtered, concentrated in vacuo, and the crude residue was purified by silica gel chromatography (2-40% 9:1 methanol:ammonium hydroxide-chloroform). The product fractions were combined and concentrated in vacuo to afford (R)—N-(6-bromothiazolo[5,4-b]pyrazin-2-yl)-4H-1′-azaspiro[oxazole-5,3′-bicyclo[2.2.2]octan]-2-amine (200 mg, 57% yield). 1H NMR (400 MHz, CDCl3) δ ppm 9.39 (br. s., 1H) 8.48 (s, 1H) 4.05 (d, J=9.79 Hz, 1H) 3.72 (d, J=9.79 Hz, 1H) 3.42 (dd, J=15.06, 1.76 Hz, 1H) 2.73-3.08 (m, 5H) 2.10-2.22 (m, 2H) 1.73-1.84 (m, J=14.09, 9.94, 4.17, 4.17 Hz, 1H) 1.52-1.65 (m, 2H). MS (LC/MS) R.T.=1.29; [M+H]+=394.99.

Provenance & Evidence