Ethyl chloroformate → HCID 86634251, compound

Temperature

35 °C

N,N-dimethylspiro[indoline-3,4′-piperidine]-1-carboxamide 6aa (500 mg, 1928 μmol) was suspended in a mixture of DCE (1.5 mL) and DME (1.5 mL) and treated with tert-butyl 3-oxo-8-azabicyclo[3.2.1]octane-8-carboxylate 6ab (651 mg, 2892 μmol) followed by titanium(IV) isopropoxide (2.260 ml, 7712 μmol). The tube was flushed with nitrogen, capped and allowed to stir under nitrogen at 35° C. for 50 hours. The reaction was quenched with MeOH (10 mL) and cooled to −40° C. Sodium triacetoxyborohydride (817 mg, 3856 μmol) was added portionwise, and the reaction was allowed to proceed at −40° C. until vigorous bubbling subsided, and the mixture was then slowly warmed up to room temperature and allowed to stir overnight. 1N NaOH (10 mL) was added, followed by acetone (50 mL) and the suspension was stirred for 2 hours to effect complete precipitation of the titanium salts. The suspension was filtered and the filter cake was rinsed with acetone (5×20 mL). The filtrate was concentrated to evaporate most of the organic solvents and the remaining aqueous phase diluted with 1N NaOH and extracted with dichloromethane (3×75 mL). The combined organic extracts were dried on Na2SO4 and concentrated to provide the crude product. To eliminate remaining traces of starting material, the crude product was dissolved in dichloromethane (20 mL) and treated with ethyl chloroformate (1 mL) and triethyl amine (1 mL). After 30 minutes, the solution was washed with 1N NaOH (30 mL). The aqueous layer was extracted with DCM (2×50 mL) and the combined organic extracts were dried on Na2SO4 and concentrated under reduced pressure. The free base was dissolved in diethyl ether (20 mL) and treated with excess 1N HCl in ether (5 mL). The resulting suspension was filtered under nitrogen, washed with diethyl ether (3×20 mL) and vacuum dried to provide tert-butyl 3-(1-(dimethylcarbamoyl)spiro[indoline-3,4′-piperidine]-1′-yl)-8-azabicyclo[3.2.1]octane-8-carboxylate hydrochloride 6ac as a white solid (90% purity by LC/MS). LC/MS m/z 469.4 [M+H]+ retention time 2.12 minutes (10-99% CH3CN—H2O gradient with 0.03% TFA, 5 min)

1. customThe tube was flushed with nitrogen
2. customcapped
3. customThe reaction was quenched with MeOH (10 mL)
4. temperaturecooled to −40° C
5. customto proceed at −40° C.
6. customuntil vigorous bubbling
7. temperaturethe mixture was then slowly warmed up to room temperature
8. stirringto stir overnight
9. addition1N NaOH (10 mL) was added
10. stirringthe suspension was stirred for 2 hours
11. customprecipitation of the titanium salts
12. filtrationThe suspension was filtered
13. washthe filter cake was rinsed with acetone (5×20 mL)
14. concentrationThe filtrate was concentrated
15. customto evaporate most of the organic solvents
16. additionthe remaining aqueous phase diluted with 1N NaOH
17. extractionextracted with dichloromethane (3×75 mL)
18. customThe combined organic extracts were dried on Na2SO4
19. concentrationconcentrated
20. customto provide the crude product
21. waitAfter 30 minutes
22. washthe solution was washed with 1N NaOH (30 mL)
23. extractionThe aqueous layer was extracted with DCM (2×50 mL)
24. customthe combined organic extracts were dried on Na2SO4
25. concentrationconcentrated under reduced pressure
26. dissolutionThe free base was dissolved in diethyl ether (20 mL)
27. additiontreated with excess 1N HCl in ether (5 mL)
28. filtrationThe resulting suspension was filtered under nitrogen
29. washwashed with diethyl ether (3×20 mL) and vacuum
30. customdried

ORD record

ord-514f242aa37d4a8f88fec8327a8c4cfa

Source dataset

uspto-grants-2012_09

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US08263605B2