Trimethylsilyl cyanide → 2-(2-Cyclopropylpyrimidin-5-yl)-2-(4,4-difluoropiperidin-1-yl)acetonitrile

HRID 1482487Notes

Reaction equation

[CH:1]1([C:4]2[N:9]=[CH:8][C:7]([CH:10]=O)=[CH:6][N:5]=2)[CH2:3][CH2:2]1.[Si]([C:16]#[N:17])(C)(C)C.Cl.[F:19][C:20]1([F:26])[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]1.C(O[Na])(C)=O>CC(O)=O>[CH:1]1([C:4]2[N:9]=[CH:8][C:7]([CH:10]([N:23]3[CH2:24][CH2:25][C:20]([F:26])([F:19])[CH2:21][CH2:22]3)[C:16]#[N:17])=[CH:6][N:5]=2)[CH2:3][CH2:2]1

Participants

Conditions

Temperature: 30 °C

Procedure

To a solution of 2-cyclopropylpyrimidine-5-carbaldehyde (2 g, 13.5 mmol) and TMSCN (2.68 g, 27 mmol) in AcOH (30 mL) was added 4,4-difluoropiperidine hydrochloride (3.1 g, 13.5 mmol), followed by AcONa (2.66 g, 32.4 mg). The mixture was stirred at 30° C. for overnight. The solvent was removed under reduced pressure and saturated NaHCO3 (aq) was added to the mixture to pH=8. The resulting mixture was extracted with EtOAc (3×100 mL). The organic layer was dried over Na2SO4, filtered and concentrated in vacuum to give the 2-(2-cyclopropylpyrimidin-5-yl)-2-(4,4-difluoropiperidin-1-yl)acetonitrile as a light red solid (3.5 g, 93%), which was used directly for next step without further purification. 1H NMR (CDCl3 400 MHz): δ 8.69 (s, 2H), 4.88 (s, 1H), 2.73-2.70 (t, J=5.5 Hz, 4H), 2.34-2.27 (m, 1H), 2.11-2.00 (m, 4H), 1.19-1.13 (m, 4H).

Workup

customThe solvent was removed under reduced pressure and saturated NaHCO3 (aq)
additionwas added to the mixture to pH=8
extractionThe resulting mixture was extracted with EtOAc (3×100 mL)
dry with materialThe organic layer was dried over Na2SO4
filtrationfiltered
concentrationconcentrated in vacuum

Sources & evidence

ORD record: ord-5237b7d5847e4a5fabf0dd69cff3e868
Source dataset: uspto-grants-2016_08
DOI: 10.6084/m9.figshare.5104873.v1
Patent number: US09415055B2

Reaction notes

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