Triethylamine → 8-Benzyl-3,8-diaza-bicyclo[4.2.0]octane-3-carboxylic acid tert-butyl ester

To a cooled to 0° C. solution of 3-benzylamino-4-hydroxymethyl-piperidine-1-carboxylic acid tert-butyl ester (3.65 g, 11.4 mmol) and triethylamine (4.77 mL, 34.2 mmol) in THF (60 mL), was added drop-wise methane sulfonyl chloride (1.7 g, 14.8 mmol) at 0° C. The reaction mixture was warmed to room temperature and stirred for 1 h, then Cs2CO3 (5.0 g, 15.4 mmol) was added. The reaction mixture was heated to 60° C. for 18 h. The reaction mixture was cooled to ambient temperature and filtered. The filtrate was washed with H2O (2×100 mL), the organic layer was separated and the aqueous layer was extracted with EtOAc (2×100 mL). The combined organics were dried (Na2SO4), filtered, and concentrated under reduced pressure to yield the crude title compound (3.38 g). The crude product was purified (FCC, SiO2, 4% acetone, dichloromethane) to yield pure title compound (2.88 g, 84%). MS (ESI) mass calcd. for C18H26N2O2, 302.42; m/z found, 303.2 [M+H]+. 1H NMR (CDCl3): 7.35-7.15 (m, 5H), 4.02-2.80 (m, 9H), 2.48-2.36 (m, 1H), 1.95-1.65 (m, 2H), 1.56-1.32 (m, 10H).

1. temperatureThe reaction mixture was heated to 60° C. for 18 h
2. temperatureThe reaction mixture was cooled to ambient temperature
3. filtrationfiltered
4. washThe filtrate was washed with H2O (2×100 mL)
5. customthe organic layer was separated
6. extractionthe aqueous layer was extracted with EtOAc (2×100 mL)
7. dry with materialThe combined organics were dried (Na2SO4)
8. filtrationfiltered
9. concentrationconcentrated under reduced pressure
10. customto yield the crude title compound (3.38 g)
11. customThe crude product was purified (FCC, SiO2, 4% acetone, dichloromethane)

ORD record

ord-3d5537d85e964ef8a25dfbeb4694bcd9

Source dataset

uspto-grants-2015_06

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US09062044B2