Potassium Carbonate → 1-[3-(4-Bromophenoxy)propyl]-4,4-difluoropiperidine

HRID 84221Notes

Reaction equation

[Br:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH2:9][CH2:10][CH2:11]Br)=[CH:4][CH:3]=1.Cl.[F:14][C:15]1([F:21])[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]1.C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH2:9][CH2:10][CH2:11][N:18]2[CH2:19][CH2:20][C:15]([F:21])([F:14])[CH2:16][CH2:17]2)=[CH:4][CH:3]=1

Participants

Conditions

Temperature: 60 °C

Procedure

A suspension of 1-bromo-4-(3-bromopropoxy)benzene (1.85 g, 6.29 mmol), 4,4-difluoropiperidine hydrochloride (1.0 g, 6.34 mmol) and potassium carbonate (2.17 g, 15.7 mmol) in acetonitrile (100 mL) was heated to 60° C. overnight, then concentrated in vacuo. The residue was partitioned between ether and saturated aqueous sodium bicarbonate. The layers were separated; the organic layer was washed with saturated aqueous sodium bicarbonate, water and brine. The organic layer was dried (Na2SO4), filtered and concentrated. Purification by flash column chromatography on an analogix SF40-80g column (hexanes/ethyl acetate=7:3) afforded the title compound as a clear oil (1.07 g, 50%). LCMS m/z 334.3 (M+1). 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.90-2.08 (m, 6 H) 2.47-2.64 (m, 6 H) 3.99 (t, J=6.34 Hz, 2 H) 6.75-6.81 (m, 2 H) 7.34-7.40 (m, 2 H).

Workup

concentrationconcentrated in vacuo
customThe residue was partitioned between ether and saturated aqueous sodium bicarbonate
customThe layers were separated
washthe organic layer was washed with saturated aqueous sodium bicarbonate, water and brine
dry with materialThe organic layer was dried (Na2SO4)
filtrationfiltered
concentrationconcentrated
customPurification by flash column chromatography on an analogix SF40-80g column (hexanes/ethyl acetate=7:3)

Sources & evidence

ORD record: ord-78259b0fda7c4bb19238e366a79709b8
Source dataset: uspto-grants-2014_09
DOI: 10.6084/m9.figshare.5104873.v1
Patent number: US08846933B2

Reaction notes

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