Diisopropylethylamine → Isopropyl 2-(5-bromo-2,6-dimethyl-4-(4-(trifluoromethyl)piperidin-1-yl)pyridin-3-yl)-2-oxoacetate

HRID 718393Notes

Reaction equation

HRID 718393 reaction equation
Cl.[F:2][C:3]([F:11])([F:10])[CH:4]1[CH2:9][CH2:8][NH:7][CH2:6][CH2:5]1.CCN(C(C)C)C(C)C.[Br:21][C:22]1[C:23](Cl)=[C:24]([C:30](=[O:37])[C:31]([O:33][CH:34]([CH3:36])[CH3:35])=[O:32])[C:25]([CH3:29])=[N:26][C:27]=1[CH3:28]>CC#N.CCOCC>[Br:21][C:22]1[C:23]([N:7]2[CH2:8][CH2:9][CH:4]([C:3]([F:11])([F:10])[F:2])[CH2:5][CH2:6]2)=[C:24]([C:30](=[O:37])[C:31]([O:33][CH:34]([CH3:35])[CH3:36])=[O:32])[C:25]([CH3:29])=[N:26][C:27]=1[CH3:28]

Participants

6

Reactant 3

HCID 81531DiisopropylethylamineHCID 162181604-(Trifluoromethyl)piperidine hydrochlorideHCID 118307804HCID 118307804, compound

Product 1

HCID 118307679Isopropyl 2-(5-bromo-2,6-dimethyl-4-(4-(trifluoromethyl)piperidin-1-yl)pyridin-3-yl)-2-oxoacetateYield 71.6%

Reagents, catalysts & solvents 2

HCID 3283Diethyl EtherSolventHCID 6342AcetonitrileSolvent

Conditions

Temperature
80 °C

Procedure

To a solution of 4-(trifluoromethyl)piperidine HCl (1.7 g, 8.97 mmol) and DIEA (3.13 mL, 17.9 mmol) in anhydrous CH3CN (15 mL) was added isopropyl 2-(5-bromo-4-chloro-2,6-dimethylpyridin-3-yl)-2-oxoacetate (3.0 g, 8.97 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 (5-20% EtOAc/hexanes) using an Isolera chromatography station to give isopropyl 2-(5-bromo-2,6-dimethyl-4-(4-(trifluoromethyl)piperidin-1-yl)pyridin-3-yl)-2-oxoacetate 2.9 g (71%). 1H NMR (500 MHz, CDCl3) δ 5.25-5.20 (m, 1H), 3.54-3.51 (m, 2H), 3.15 (dt, J=12.5, 2.0 Hz, 2H), 2.87 (s, 3H), 2.57 (s, 3H), 2.30-2.23 (m, 1H), 2.02-1.99 (m, 2H), 1.79 (dq, J=12.4, 4.1 Hz, 2H) 1.43 (d, J=6.2 Hz, 6H). UPLC (M+H)=453.2.

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 (5-20% EtOAc/hexanes)

Sources & evidence

ORD record
ord-9aef4576dc4a4fcaa1fb129c81507d0b
Source dataset
uspto-grants-2015_11
Patent number
US09193720B2

Reaction notes

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