4-Methylpiperidine → Isopropyl 2-(5-bromo-2,6-dimethyl-4-(4-methylpiperidin-1-yl)pyridin-3-yl)-2-oxoacetate

HRID 718399Notes

Reaction equation

[CH3:1][CH:2]1[CH2:7][CH2:6][NH:5][CH2:4][CH2:3]1.CCN(C(C)C)C(C)C.[Br:17][C:18]1[C:19](Cl)=[C:20]([C:26](=[O:33])[C:27]([O:29][CH:30]([CH3:32])[CH3:31])=[O:28])[C:21]([CH3:25])=[N:22][C:23]=1[CH3:24]>CC#N.CCOCC>[Br:17][C:18]1[C:19]([N:5]2[CH2:6][CH2:7][CH:2]([CH3:1])[CH2:3][CH2:4]2)=[C:20]([C:26](=[O:33])[C:27]([O:29][CH:30]([CH3:31])[CH3:32])=[O:28])[C:21]([CH3:25])=[N:22][C:23]=1[CH3:24]

Participants

Conditions

Temperature: 80 °C

Procedure

To a solution of 4-methylpiperidine (593 mg, 5.98 mmol) and DIEA (2.1 mL, 12 mmol) in anhydrous CH3CN (15 mL) was added isopropyl 2-(5-bromo-4-chloro-2,6-dimethylpyridin-3-yl)-2-oxoacetate (2.0 g, 5.98 mmol) at rt. The resulting mixture was placed in a pre-heated oil bath (80° C.) and stirred for 24 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 gave isopropyl 2-(5-bromo-2,6-dimethyl-4-(4-methylpiperidin-1-yl)pyridin-3-yl)-2-oxoacetate 1.99 g (84%). 1H NMR (500 MHz, DMSO-d6) δ 5.08-5.03 (m, 1H), 3.41-3.39 (m, 2H), 2.83 (br. s, 2H), 2.60 (s, 3H), 2.29 (s, 3H), 1.58 (d, J=12.5 Hz, 2H), 1.44 (br. s, 1H), 1.29 (d, J=6.2 Hz, 6H), 1.09-1.07 (m, 2H), 0.92 (d, J=6.2 Hz, 3H). UPLC (M+H)=399.2.

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-5e43603b93c04bee9811d1f78a7afb7c
Source dataset: uspto-grants-2015_11
DOI: 10.6084/m9.figshare.5104873.v1
Patent number: US09193720B2

Reaction notes

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