反应详情

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).

1. temperaturecooled to −40° C. to −50° C
2. stirringto stir at −40° C.
3. customuntil bubbling
4. custom(approximately 3 h)
5. temperatureto warm slowly back to room temperature
6. stirringwas stirred for 2 h
7. filtrationThe sticky suspension was filtered through a pad of Celite
8. washthe filter cake was washed with MeOH (2×30 mL) and Et2O (3×50 mL)
9. customThe filtrate was separated into the corresponding layers
10. extractionthe aqueous layer was extracted with Et2O (2×50 mL)
11. dry with materialThe combined organic extracts were dried over Na2SO4
12. concentrationconcentrated
13. customto provide the crude product as a white foam
14. waitAfter 10 min
15. filtrationThe biphasic suspension was filtered
16. washthe precipitate was washed with HCl 1N (2×30 mL), H2O (2×30 mL) and Et2O (3×30 mL)
17. customdried