4-Benzylpiperidine → Isopropyl 2-(4-(4-benzylpiperidin-1-yl)-5-bromo-2,6-dimethylpyridin-3-yl)-2-oxoacetate

HRID 718414Notes

Reaction equation

HRID 718414 reaction equation
[CH2:1]([CH:8]1[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CCN(C(C)C)C(C)C.[Br:23][C:24]1[C:25](Cl)=[C:26]([C:32](=[O:39])[C:33]([O:35][CH:36]([CH3:38])[CH3:37])=[O:34])[C:27]([CH3:31])=[N:28][C:29]=1[CH3:30]>CC#N.CCOCC>[CH2:1]([CH:8]1[CH2:13][CH2:12][N:11]([C:25]2[C:24]([Br:23])=[C:29]([CH3:30])[N:28]=[C:27]([CH3:31])[C:26]=2[C:32](=[O:39])[C:33]([O:35][CH:36]([CH3:37])[CH3:38])=[O:34])[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1

Participants

6

Reactant 3

HCID 317384-BenzylpiperidineHCID 81531DiisopropylethylamineHCID 118307804Isopropyl 2-(5-bromo-4-chloro-2,6-dimethylpyridin-3-yl)-2-oxoacetate

Product 1

HCID 118307762Isopropyl 2-(4-(4-benzylpiperidin-1-yl)-5-bromo-2,6-dimethylpyridin-3-yl)-2-oxoacetateYield 68.6%

Reagents, catalysts & solvents 2

HCID 3283Diethyl EtherSolventHCID 6342AcetonitrileSolvent

Conditions

Temperature
80 °C

Procedure

To a solution of 4-benzylpiperidine (0.80 g, 4.56 mmol) and DIEA (2.4 mL, 13.7 mmol) in anhydrous CH3CN (30 mL) was added isopropyl 2-(5-bromo-4-chloro-2,6-dimethylpyridin-3-yl)-2-oxoacetate (1.7 g, 4.56 mmol) at rt. The resulting mixture was placed in a pre-heated oil bath (80° C.) and stirred for 18 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 (0-25% EtOAc/hexanes) using an Isolera chromatography station gave isopropyl 2-(4-(4-benzylpiperidin-1-yl)-5-bromo-2,6-dimethylpyridin-3-yl)-2-oxoacetate 1.48 g (68%). 1H NMR (500 MHz, DMSO-d6) δ 7.3-7.27 (m, 2H), 7.20-7.15 (m, 3H), 5.09-5.04 (m, 1H), 3.23 (br. s, 2H), 2.84 (br. s, 2H), 2.59 (s, 3H), 2.51-2.49 (m, 2H), 2.28 (s, 3H), 1.61 (br. s, 1), 1.55 (d, J=13.6 Hz, 2H), 1.30 (d, J=6.2 Hz, 6H), 1.14 (br. s, 2H). UPLC (M+H)=475.2.

Workup

  1. customThe resulting mixture was placed in a pre-heated oil bath
  2. temperaturecooled
  3. washwashed with water, brine
  4. dry with materialdried (MgSO4)
  5. additionThe crude product was charged (DCM) to a 80 g ISCO silica gel cartridge and gradient
  6. washeluted (0-25% EtOAc/hexanes)

Sources & evidence

ORD record
ord-9053bf5437ba427099f60252dcd19c3c
Source dataset
uspto-grants-2015_11
Patent number
US09193720B2

Reaction notes

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