Triethylamine → tert-butyl 1'-(8-(ethoxycarbonyl)-8-azabicyclo[3.2.1]octan-3-yl)-1H-spiro[isoquinoline-4,4'-piperidine]-2(3H)-carboxylate

Participants

Reaction Steps

tert-Butyl 1H-spiro[isoquinoline-4,4′-piperidine]-2(3H)-carboxylate 5a (2.071 g, 6.11 mmol) and ethyl 3-oxo-8-azabicyclo[3.2.1]octane-8-carboxylate (1.51 g, 7.66 mmol) were dissolved in anhydrous dichloromethane (10 mL) in a 100-mL round-bottom flask and treated with triethylamine (618 mg, 6.11 mmol), followed by titanium tetraisopropoxide (5.21 g, 18.3 mmol). The reaction was stirred under nitrogen at room temperature for 21 h, then cooled in a dry ice/isopropanol bath to −40° C. and quenched with methanol (10 mL). The reaction was stirred for several minutes at the same temperature and treated in one portion with sodium borohydride (462 mg, 12.2 mmol). The reaction was stirred at −40° C. for 30 minutes, then warmed to room temperature. The reaction was then treated with 1 N NaOH (12 mL), diluted with methanol (50 mL) and stirred vigorously at room temperature for 10 minutes. The reaction was filtered through Celite and the solids rinsed with dichloromethane (4×25 mL). The filtrate was washed with H2O, saturated brine, dried over Na2SO4 and filtered. The filtrate was concentrated under reduced pressure to afford 3.641 g tert-butyl 1′-(8-(ethoxycarbonyl)-8-azabicyclo[3.2.1]octan-3-yl)-1H-spiro[isoquinoline-4,4′-piperidine]-2(3H)-carboxylate 5b as a pale yellow oil. LC/MS m/z [M+H]+ 484.3, retention time 2.32 min (10-99% CH3CN—H2O gradient, with 0.05% TFA, 5 min).

Provenance & Evidence