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

HRID 718386Notes

Reaction equation

[C:1]1([CH:7]2[CH2:12][CH2:11][NH:10][CH2:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CCN(C(C)C)C(C)C.[Br:22][C:23]1[C:24](Cl)=[C:25]([C:31](=[O:38])[C:32]([O:34][CH:35]([CH3:37])[CH3:36])=[O:33])[C:26]([CH3:30])=[N:27][C:28]=1[CH3:29]>CC#N>[Br:22][C:23]1[C:24]([N:10]2[CH2:9][CH2:8][CH:7]([C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)[CH2:12][CH2:11]2)=[C:25]([C:31](=[O:38])[C:32]([O:34][CH:35]([CH3:36])[CH3:37])=[O:33])[C:26]([CH3:30])=[N:27][C:28]=1[CH3:29]

Participants

Conditions

Temperature: 80 °C

Procedure

To a solution of 4-phenylpiperidine (1.25 g, 7.75 mmol) and DIEA (4.1 mL, 23.3 mmol) in anhydrous CH3CN (40 mL) was added isopropyl 2-(5-bromo-4-chloro-2,6-dimethylpyridin-3-yl)-2-oxoacetate (2.59 g, 7.75 mmol) at rt. The resulting mixture was placed in a pre-heated oil bath (80° C.) and stirred for 24 h; concentrated, and 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-2,6-dimethyl-4-(4-phenylpiperidin-1-yl)pyridin-3-yl)-2-oxoacetate 2.63 g (74%). 1H NMR (500 MHz, DMSO-d6) δ 7.34-7.31 (m, 2H), 7.25-7.20 (m, 3H), 5.11-5.06 (m, 1H), 3.50 (br. s, 2H), 2.94 (br. s, 2H), 2.68-2.63 (m, 1H), 2.63 (s, 3H), 2.13 (s, 3H), 1.81-1.78 (m, 2H), 1.60 (br. s, 2H), 1.26 (d, J=6.2 Hz, 6H). UPLC (M+H)=461.05.

Workup

customThe resulting mixture was placed in a pre-heated oil bath
concentrationconcentrated
additioncharged (DCM) to a 80 g ISCO silica gel cartridge and gradient
washeluted (5-35% EtOAc/hexanes)

Sources & evidence

ORD record: ord-43a5149ccfba431390d582f2945771d1
Source dataset: uspto-grants-2015_11
DOI: 10.6084/m9.figshare.5104873.v1
Patent number: US09193720B2

Reaction notes

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