反应条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.
实验步骤: tert-Butyl 1H-spiro[isoquinoline-4,4′-piperidine]-2(3H)-carboxylate 4a (2.80 g, 8.263 mmol) and benzyl 3-oxo-8-azabicyclo[3.2.1]octane-8-carboxylate (2.014 g, 7.767 mmol) were dissolved in a mixture of DCE (10 mL) and DME (10 mL) and placed under a nitrogen atmosphere. Triethylamine (1.149 mL, 834.5 mg, 8.263 mmol) was added, followed by Ti(OiPr)4 (7.2 mL, 6.9 g, 24.6 mmol) and the reaction was allowed to stir at room temperature for 60 h. The reaction mixture was diluted with 30 mL MeOH and cooled to −40° C. to −50° C. NaBH4 (1.223 g, 33.051 mmol, 4.0 eq) was added portion-wise over 30 min and the reaction was allowed to stir at −40° C. until bubbling had subsided (approximately 3 h), was allowed to warm slowly back to room temperature and was stirred for 2 h. The sticky suspension was filtered through a pad of Celite, and the filter cake was washed with MeOH (2×30 mL) and Et2O (3×50 mL). The filtrate was separated into the corresponding layers, and the aqueous layer was extracted with Et2O (2×50 mL). The combined organic extracts were dried over Na2SO4 and concentrated to provide the crude product as a white foam. Unreacted starting material was converted to the corresponding ethyl carbamates by suspending the crude product in CH3CN (30 mL) and treating sequentially with ethyl chloroformate (1 mL) and triethylamine (2 mL). After 10 min, the mixture was diluted with Et2O (300 mL) and poured onto 1N aq HCl (300 mL). The biphasic suspension was filtered, and the precipitate was washed with HCl 1N (2×30 mL), H2O (2×30 mL) and Et2O (3×30 mL) and dried to provide tert-butyl 1′-(8-(benzyloxycarbonyl)-8-azabicyclo[3.2.1]octan-3-yl)-1H-spiro[isoquinoline-4,4′-piperidine]-2(3H)-carboxylate 4b as the hydrochloride salt (2.7 g, 56% yield). LC/MS m/z [M+H]+ 546.4, retention time 2.92 min (10-99% CH3CN—H2O gradient, with 0.05% TFA, 5 min).
cooled to −40° C. to −50° C
to stir at −40° C.
until bubbling
(approximately 3 h)
to warm slowly back to room temperature
was stirred for 2 h
The sticky suspension was filtered through a pad of Celite
the filter cake was washed with MeOH (2×30 mL) and Et2O (3×50 mL)
The filtrate was separated into the corresponding layers
the aqueous layer was extracted with Et2O (2×50 mL)
The combined organic extracts were dried over Na2SO4
concentrated
to provide the crude product as a white foam
After 10 min
The biphasic suspension was filtered
the precipitate was washed with HCl 1N (2×30 mL), H2O (2×30 mL) and Et2O (3×30 mL)
dried
来源 ID: ord-39cd82691d8c4bc3b2d5687144cd9dbd