Sodium hydride → 3-[(1-Methylpiperidin-3-yl)oxy]benzonitrile

HRID 2239339Notes

Reaction equation

[CH3:1][N:2]1[CH2:7][CH2:6][CH2:5][CH:4]([OH:8])[CH2:3]1.[H-].[Na+].F[C:12]1[CH:13]=[C:14]([CH:17]=[CH:18][CH:19]=1)[C:15]#[N:16]>CN(C=O)C>[CH3:1][N:2]1[CH2:7][CH2:6][CH2:5][CH:4]([O:8][C:12]2[CH:13]=[C:14]([CH:17]=[CH:18][CH:19]=2)[C:15]#[N:16])[CH2:3]1

Participants

Conditions

Temperature: 0 °C

Procedure

1-Methylpiperidin-3-ol (500 mg, 4.341 mmol) was dissolved in DMF (10 ml) and cooled to 0° C. NaH (312 mg, 6.52 mmol) was added in small portions, stirred for 30 minutes and 3-fluorobenzonitrile (557 μl, 5.21 mmol) was subsequently added. The mixture was allowed to reach r.t. over 1 h and stirred for a further 16 h. Cooled to 0° C. and quenched with water. The reaction mixture was separated between water (150 ml) and DCM (2×150 ml). The combined organics were washed with water (150 ml), dried through a phase separator and evaporated in vacuo. Purification by flash silica gel chromatography using a 40 g Biotage column with a gradient of 10-100% EtOAc/MeOH/TEA 100:10:1 in heptane yielded the title compound as a colorless oil. Yield: 0.628 g (56%). 1H NMR (400 MHz, CDCl3) δ 7.32 (dt, 1H, J=7.6 Hz, J=0.9 Hz), 7.19 (m, 1H), 7.16-7.11 (m, 2H), 4.36 (m, 1H, J=4.0 Hz), 2.84 (m, 1H), 2.55 (m, 1H), 2.30-2.11 (m, 5H), 1.94 (m, 1H), 1.82 (m, 1H), 1.67-1.43 (m, 2H).

Workup

waitto reach r.t. over 1 h
stirringstirred for a further 16 h
temperatureCooled to 0° C.
customquenched with water
customThe reaction mixture was separated between water (150 ml) and DCM (2×150 ml)
washThe combined organics were washed with water (150 ml)
customdried through a phase separator
customevaporated in vacuo
customPurification by flash silica gel chromatography

Sources & evidence

ORD record: ord-c050acafd54b47fbab8ede9ab4599dca
Source dataset: uspto-grants-2010_05
DOI: 10.6084/m9.figshare.5104873.v1
Patent number: US07723331B2

Reaction notes

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