Triethylamine → 4-((3,6-difluoropyridin-2-ylamino)methyl)tetrahydro-2H-pyran-4-carbonitrile

HRID 1963837Notes

Reaction equation

F[C:2]1[C:7]([F:8])=[CH:6][CH:5]=[C:4]([F:9])[N:3]=1.[NH2:10][CH2:11][C:12]1([C:18]#[N:19])[CH2:17][CH2:16][O:15][CH2:14][CH2:13]1.C(N(CC)CC)C>CS(C)=O>[F:8][C:7]1[C:2]([NH:19][CH2:18][C:12]2([C:11]#[N:10])[CH2:17][CH2:16][O:15][CH2:14][CH2:13]2)=[N:3][C:4]([F:9])=[CH:5][CH:6]=1

Participants

Conditions

Temperature: 105 °C

Procedure

To 2,3,6-Trifluoropyridine (0.6 g, 4.5 mmol) in DMSO (5 ml) at room temperature was added 4-(aminomethyl)tetrahydro-2H-pyran-4-carbonitrile (Intermediate R, 1.01 g, 7.23 mmol) and triethylamine (1.57 ml, 11.24 mmol) sequentially. The light brown mixture was heated at 105° C. in a sealed glass bomb for 18 hours. After cooled to room temperature the reaction mixture was extracted with EtOAc (40 ml), washed with saturated NaHCO3 solution and brine, dried over sodium sulfate and concentrated in vacuo to give a light brown liquid. This crude material was purified by silica gel chromatography using a 12 g column, eluting with 5%-20% ethyl acetate in hexane to afford 550 mg (48.2% yield) of the desired product. LCMS (m/z): 254.1 [M+H]+; retention time=0.743 min. 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.69-1.95 (m, 4 H) 3.60-3.82 (m, 4 H) 4.00 (ddd, J=12.13, 4.30, 1.96 Hz, 2 H) 5.02 (br. S., 1 H) 6.12 (td, J=5.58, 2.54 Hz, 1 H) 7.19-7.33 (m, 1 H).

Workup

temperatureAfter cooled to room temperature the reaction mixture
extractionwas extracted with EtOAc (40 ml)
washwashed with saturated NaHCO3 solution and brine
dry with materialdried over sodium sulfate
concentrationconcentrated in vacuo
customto give a light brown liquid
customThis crude material was purified by silica gel chromatography
washeluting with 5%-20% ethyl acetate in hexane

Sources & evidence

ORD record: ord-2eba552d91b746e8b6343e7f8e25e6cc
Source dataset: uspto-grants-2013_04
DOI: 10.6084/m9.figshare.5104873.v1
Patent number: US08415381B2

Reaction notes

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