Hydrochloric Acid → Ethyl 3-(2-acetyl-2,3-dihydro-1h-spiro[isoquinoline-4,4'-piperidine]-1'-yl)-8-azabicyclo[3.2.1]octane-8-carboxylate

Crude ethyl 3-(2,3-dihydro-1H-spiro[isoquinoline-4,4′-piperidine]-1′-yl)-8-azabicyclo[3.2.1]octane-8-carboxylate 5c (1.00 g, 2.6 mmol) was dissolved in anhydrous dichloromethane (12 mL), cooled in an ice/H2O bath and treated dropwise with a solution of acetyl chloride (214 mg, 2.73 mmol) in anhydrous dichloromethane (2 mL). The reaction was then treated dropwise with a solution of 1.1 eq triethylamine (289 mg, 2.86 mmol) in anhydrous dichloromethane (2 mL) and stirred in the ice/H2O bath for 30 min. The reaction was diluted with EtOAc (50 mL) and washed with 50% saturated NaHCO3 (3×20 mL), saturated brine, dried over Na2SO4, and filtered. The filtrate was concentrated under reduced pressure to afford 1.063 g crude product as a pale yellow oil. The crude product was purified by reverse-phase HPLC (2-99% CH3CN—H2O gradient with 0.03% TFA, 15 min). The combined pure fractions were concentrated under reduced pressure and treated with 1 N NaOH (25 mL). The product was extracted with dichloromethane (2×50 mL) and the combined extracts washed with saturated brine, dried (Na2SO4) and filtered and concentrated. The free base was dissolved in anhydrous diethyl ether (˜10 mL) and treated with 1.0 eq HCl (500 μL 2 N ethereal HCl). The suspension was cooled in an ice/H2O bath, filtered, rinsed with Et2O (3×10 mL) and dried to provide ethyl 3-(2-acetyl-2,3-dihydro-1H -spiro[isoquinoline-4,4′-piperidine]-1′-yl)-8-azabicyclo[3.2.1]octane-8-carboxylate. LC/MS m/z [M+H]+ 426.2 retention time 1.89 min (10-99% CH3CN—H2O gradient, with 0.05% TFA, 5 min). 1H-NMR (400 MHz, DMSO-d6) δ 10.88 (br s, 1H), 7.46 (d, J=7.5 Hz, 1H), 7.23 (m, 3H), 4.70 (s, 2H), 4.25 (br s, 2H), 4.05 (br q, 2H), 3.81 (s, 2H), 3.78 (m, 1H), 3.46 (m, 3H), 3.12 (br m, 2H), 2.46 (br m, 1H), 2.13 (s, 3H), 2.12 (br s, 2H), 1.87 (br m, 4H), 1.69 (br m, 4H), 1.21 (t, J=7.1 Hz, 3H).

1. temperaturecooled in an ice/H2O bath
2. washwashed with 50% saturated NaHCO3 (3×20 mL), saturated brine
3. dry with materialdried over Na2SO4
4. filtrationfiltered
5. concentrationThe filtrate was concentrated under reduced pressure
6. customto afford 1.063 g crude product as a pale yellow oil
7. customThe crude product was purified by reverse-phase HPLC (2-99% CH3CN—H2O gradient with 0.03% TFA, 15 min)
8. concentrationThe combined pure fractions were concentrated under reduced pressure
9. additiontreated with 1 N NaOH (25 mL)
10. extractionThe product was extracted with dichloromethane (2×50 mL)
11. washthe combined extracts washed with saturated brine
12. dry with materialdried (Na2SO4)
13. filtrationfiltered
14. concentrationconcentrated
15. dissolutionThe free base was dissolved in anhydrous diethyl ether (˜10 mL)
16. temperatureThe suspension was cooled in an ice/H2O bath
17. filtrationfiltered
18. washrinsed with Et2O (3×10 mL)
19. customdried

ORD record

ord-c5622ce634f540119afd79a07d89643d

Source dataset

uspto-grants-2011_01

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US07863449B2