Diisopropylethylamine → Isopropyl 2-(5-bromo-4-(4-cyano-4-methylpiperidin-1-yl)-2,6-dimethylpyridin-3-yl)-2-oxoacetate

HRID 718407Notes

Reaction equation

CC[N:3]([CH:7]([CH3:9])C)[CH:4]([CH3:6])C.[Br:10][C:11]1[C:12](Cl)=[C:13]([C:19](=[O:26])[C:20]([O:22][CH:23]([CH3:25])[CH3:24])=[O:21])[C:14]([CH3:18])=[N:15][C:16]=1[CH3:17]>CC#N.CCOCC>[Br:10][C:11]1[C:12]([N:3]2[CH2:4][CH2:6][C:13]([C:14]#[N:15])([CH3:12])[CH2:9][CH2:7]2)=[C:13]([C:19](=[O:26])[C:20]([O:22][CH:23]([CH3:25])[CH3:24])=[O:21])[C:14]([CH3:18])=[N:15][C:16]=1[CH3:17]

Participants

Conditions

Temperature: 80 °C

Procedure

To a solution of 4-methylpiperidine-4-carbonitrile, HCl (1.0 g, 6.22 mmol) and DIEA (4.4 mL, 24.9 mmol) in anhydrous CH3CN (30 mL) was added isopropyl 2-(5-bromo-4-chloro-2,6-dimethylpyridin-3-yl)-2-oxoacetate (2.1 g, 6.22 mmol) at rt. The resulting mixture was placed in a pre-heated oil bath (80° C.) and stirred for 72 h; cooled, diluted with ether, washed with water, brine, and dried (MgSO4). The crude product was charged (DCM) to a 80 g ISCO silica gel cartridge and gradient eluted (5-35% EtOAc/hexanes) using an Isolera chromatography station to give isopropyl 2-(5-bromo-4-(4-cyano-4-methylpiperidin-1-yl)-2,6-dimethylpyridin-3-yl)-2-oxoacetate 1.0 g (38%). 1H NMR (500 MHz, DMSO-d6) δ 5.08-5.03 (m, 1H), 3.54-3.40 (m, 4H), 2.61 (s, 3H), 2.30 (s, 3H), 1.92 (d, J=12.4 Hz, 2H), (2H missing), 1.35 (s, 3H), 1.28 (d, J=5.9 Hz, 6H). UPLC (M+H)=424.3.

Workup

customThe resulting mixture was placed in a pre-heated oil bath
temperaturecooled
washwashed with water, brine
dry with materialdried (MgSO4)
additionThe crude product was charged (DCM) to a 80 g ISCO silica gel cartridge and gradient
washeluted (5-35% EtOAc/hexanes)

Sources & evidence

ORD record: ord-283472ba5c534e65b62b31fb96c84519
Source dataset: uspto-grants-2015_11
DOI: 10.6084/m9.figshare.5104873.v1
Patent number: US09193720B2

Reaction notes

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