Triethylamine → 6-Amino-4-(4-((dimethylamino)methyl)-4-hydroxypiperidin-1-yl)nicotinonitrile

HRID 1777945Notes

Reaction equation

[CH3:1][N:2]([CH2:4][C:5]1([OH:11])[CH2:10][CH2:9][NH:8][CH2:7][CH2:6]1)[CH3:3].[NH2:12][C:13]1[CH:20]=[C:19](F)[C:16]([C:17]#[N:18])=[CH:15][N:14]=1.C(N(CC)CC)C>CCO>[NH2:12][C:13]1[CH:20]=[C:19]([N:8]2[CH2:7][CH2:6][C:5]([CH2:4][N:2]([CH3:1])[CH3:3])([OH:11])[CH2:10][CH2:9]2)[C:16]([C:17]#[N:18])=[CH:15][N:14]=1

Participants

Conditions

Temperature: 80 °C

Procedure

A mixture of 4-[(dimethylamino)methyl]-4-piperidinol (1.0 g, 4.33 mmol), 6-amino-4-fluoronicotinonitrile (intermediate 21, 593 mg, 4.33 mmol) and triethylamine (3.62 ml, 26.00 mmol) was heated at 80° C. in a septum sealed reaction vessel under argon for 28 h. The reaction mixture was cooled, EtOH (5 ml) added and heated at 80° C. for 18 h. The reaction mixture was then evaporated, partitioned between aqueous NaHCO3 solution and DCM, extracted 5× with DCM containing 10% MeOH, the combined DCM layers dried over MgSO4 and evaporated. The residue was triturated with Et2O (20 ml) and DCM (1 ml) to give the title compound as a beige solid. 1H NMR (400 MHz, CDCl3) δ 8.15 (s, 1H), 5.82 (s, 1H), 4.70 (s, br, 2H), 3.65-3.58 (m, 2H), 3.27-3.20 (m, 2H), 2.38 (s, 6H), 2.26 (s, 2H), 1.68-1.62 (m, 4H). (UPLC-MS 6) tR 0.25; ESI-MS 276.3 [M+H]+.

Workup

customsealed
customreaction vessel under argon for 28 h
temperatureThe reaction mixture was cooled
temperatureheated at 80° C. for 18 h
customThe reaction mixture was then evaporated
custompartitioned between aqueous NaHCO3 solution and DCM
extractionextracted 5× with DCM containing 10% MeOH
dry with materialthe combined DCM layers dried over MgSO4
customevaporated
customThe residue was triturated with Et2O (20 ml) and DCM (1 ml)

Sources & evidence

ORD record: ord-1817eafab8af47808ee01fe553d67bc9
Source dataset: uspto-grants-2016_02
DOI: 10.6084/m9.figshare.5104873.v1
Patent number: US09266883B2

Reaction notes

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