Triethylamine → tert-Butyl 4-(4-((4-((2-(2-methoxy-2-oxoethyl)phenyl)ethynyl)-5-(trifluoromethyl)pyrimidin-2-yl)amino)benzyl)piperazine-1-carboxylate

HRID 1485228Notes

Reaction equation

HRID 1485228 reaction equation
Cl[C:2]1[C:7]([C:8]([F:11])([F:10])[F:9])=[CH:6][N:5]=[C:4]([NH:12][C:13]2[CH:32]=[CH:31][C:16]([CH2:17][N:18]3[CH2:23][CH2:22][N:21]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH2:20][CH2:19]3)=[CH:15][CH:14]=2)[N:3]=1.[C:33]([C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][C:36]=1[CH2:41][C:42]([O:44][CH3:45])=[O:43])#[CH:34].C(N(CC)CC)C>CN(C=O)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I>[CH3:45][O:44][C:42](=[O:43])[CH2:41][C:36]1[CH:37]=[CH:38][CH:39]=[CH:40][C:35]=1[C:33]#[C:34][C:2]1[C:7]([C:8]([F:11])([F:10])[F:9])=[CH:6][N:5]=[C:4]([NH:12][C:13]2[CH:32]=[CH:31][C:16]([CH2:17][N:18]3[CH2:23][CH2:22][N:21]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH2:20][CH2:19]3)=[CH:15][CH:14]=2)[N:3]=1

Participants

7

Reactant 3

HCID 8471TriethylamineHCID 45789861Methyl 2-(2-ethynylphenyl)acetateHCID 86675725tert-Butyl 4-(4-((4-chloro-5-(trifluoromethyl)pyrimidin-2-yl)amino)benzyl)piperazine-1-carboxylate

Product 1

HCID 71229655tert-Butyl 4-(4-((4-((2-(2-methoxy-2-oxoethyl)phenyl)ethynyl)-5-(trifluoromethyl)pyrimidin-2-yl)amino)benzyl)piperazine-1-carboxylateYield 30%

Reagents, catalysts & solvents 3

HCID 24350Copper(1+) iodide; Copper(I) iodide; Cuprous iodide; Cuprous iodide (CuI)CatalystHCID 178418476HCID 178418476, compoundCatalystHCID 6228DimethylformamideSolvent

Conditions

Temperature
100 °C

Procedure

tert-Butyl 4-(4-((4-chloro-5-(trifluoromethyl)pyrimidin-2-yl)amino)benzyl)piperazine-1-carboxylate (I94) (0.500 g, 1.06 mmol) and methyl 2-(2-ethynylphenyl)acetate (I4) (0.203 g, 1.17 mmol) were dissolved in DMF (10 mL) and bis(triphenylphosphine)palladium(II) chloride (37 mg, 5 mol %) was added. The mixture was degassed with nitrogen for ten minutes, then copper(I) iodide (10 mg, 5 mol %) and triethylamine (0.738 mL, 5.30 mmol) were added. The mixture was heated under microwave irradiation (100° C./20 minutes) then concentrated. Chromatography of the residue (12 g silica cartridge, 0-100% ethyl acetate/petroleum benzine 40-60° C.) gave the title compound (I95) (192 mg, 30% yield) as a brown oil; 1H NMR (400 MHz, CDCl3) δ 8.63 (s, 1H), 7.68 (dd, J=7.6, 1.0 Hz, 1H), 7.59 (d, J=8.4 Hz, 2H), 7.50 (s, 1H), 7.42 (dd, J=7.5, 1.4 Hz, 1H), 7.38-7.29 (m, 4H), 3.95 (s, 2H), 3.70 (s, 3H), 3.50 (s, 2H), 3.45-3.40 (m, 4H), 2.43-2.35 (m, 4H), 1.45 (s, 9H). LCMS Method C: rt 5.30 min; m/z 610.1 [M+H]+, m/z 608.2 [M−H]−.

Workup

  1. customThe mixture was degassed with nitrogen for ten minutes
  2. concentrationthen concentrated

Sources & evidence

ORD record
ord-28eb06d3e38a42fab9f4ecc7fd919c84
Source dataset
uspto-grants-2016_08
Patent number
US09421205B2

Reaction notes

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