p-Bromochlorobenzene → Tert-butyl 8-(4-chlorophenyl)-8-hydroxy-5-azaspiro[2.5]octane-5-carboxylate

Temperature

-78 °C

In a flame-dried 100 mL three necked flask, a solution of 1-bromo-4-chlorobenzene (3.51 g, 18.36 mmol) in THF (20 mL) was cooled to −78° C. and treated with the dropwise addition of 1.6 M BuLi in hexanes (12.00 mL, 19.19 mmol) at a rate which did not allow the temperature to exceed −60° C. The mixture was stirred at −78° C. for 1 h, during which time a white precipitate was observed. The mixture was treated with the dropwise addition of a solution of tert-butyl 8-oxo-5-azaspiro[2.5]octane-5-carboxylate (1.88 g, 8.35 mmol) in THF (5 mL), at a rate which did not allow the temperature to exceed −60° C. The mixture was stirred for 3 h, then allowed to warm to −20° C. and quenched with saturated ammonium chloride solution. The mixture was extracted 3× with ethyl acetate, the combined organic phases were washed with water followed by brine, then dried over sodium sulfate and concentrated in-vacuo. The residue was purified over a 5×15 cm silica gel column, eluting with ethyl acetate/hexanes (5%-10%-15%-20% ethyl acetate, to yield the title compound (1.81 g, 5.36 mmol, 64.2% yield) as a colorless powder. MS (ESI+)=264.27, (M-tBuO)+, 220 (M−H2O-Boc)+.

1. customto exceed −60° C
2. customto exceed −60° C
3. stirringThe mixture was stirred for 3 h
4. temperatureto warm to −20° C.
5. customquenched with saturated ammonium chloride solution
6. extractionThe mixture was extracted 3× with ethyl acetate
7. washthe combined organic phases were washed with water
8. dry with materialdried over sodium sulfate
9. concentrationconcentrated in-vacuo
10. customThe residue was purified over a 5×15 cm silica gel column
11. washeluting with ethyl acetate/hexanes (5%-10%-15%-20% ethyl acetate

ORD record

ord-6f51e03c1f2d49d8ac8ef4eb4e8d0db8

Source dataset

uspto-grants-2011_07

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US07985861B2