Nitrogen → 6'-Bromo-4-(difluoromethyl)spiro[cyclohexane-1,2'-inden]-1'(3'H)-one

Temperature

-20 °C

Methyl 1-(4-bromo-2-iodobenzyl)-4-(difluoromethyl)cyclohexanecarboxylate (Intermediate 90, 2.3 g, 4.72 mmol) was dissolved in THF (30 mL). The atmosphere was exchanged to N2 (g), and the solution was cooled to −20° C. Isopropylmagnesium chloride—lithium chloride (1.3M in THF, 4.00 mL, 5.19 mmol) was added dropwise over one h. The reaction mixture was stirred at −20° C. for 40 min. The reaction mixture was removed from the cooling bath, and left to warm up to r.t., while stirred for 1.5 h. The reaction was stirred at r.t. overnight and then heated at 40° C. for 3 h. The reaction was cooled to r.t. and quenched with sat. NH4Cl. The resulting mixture was stirred overnight. The organic layer was collected and dried over MgSO4, filtered, and concentrated. The residue was purified by flash chromatography (0-10% EtOAc in heptane) followed by preparative chromatography to give the title compound (0.562 g, 24% yield): 1H NMR (500 MHz, DMSO-d6) δ ppm 1.46-1.65 (m, 4H), 1.75-1.96 (m, 5H), 2.93 (s, 2H), 6.00 (dt, 1H), 7.51 (d, 1H), 7.73 (d, 1H), 7.83 (dd, 1H).

1. customThe reaction mixture was removed from the cooling bath
2. waitleft
3. temperatureto warm up to r.t.
4. stirringwhile stirred for 1.5 h
5. stirringThe reaction was stirred at r.t. overnight
6. temperatureheated at 40° C. for 3 h
7. temperatureThe reaction was cooled to r.t.
8. customquenched with sat. NH4Cl
9. stirringThe resulting mixture was stirred overnight
10. customThe organic layer was collected
11. dry with materialdried over MgSO4
12. filtrationfiltered
13. concentrationconcentrated
14. customThe residue was purified by flash chromatography (0-10% EtOAc in heptane)

ORD record

ord-6e0982ed24d94822bfa4a78b6f8e8ee5

Source dataset

uspto-grants-2016_02

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US09248129B2