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

HRID 1473052Notes

Reaction equation

HRID 1473052 reaction equation
[C:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[CH2:9][C:10]([NH2:12])=[O:11])#[CH:2].Cl[C:14]1[C:19]([C:20]([F:23])([F:22])[F:21])=[CH:18][N:17]=[C:16]([NH:24][C:25]2[CH:30]=[CH:29][C:28]([CH:31]3[CH2:36][CH2:35][CH2:34][CH2:33][N:32]3[C:37]([O:39][C:40]([CH3:43])([CH3:42])[CH3:41])=[O:38])=[CH:27][CH:26]=2)[N:15]=1.C(N(CC)CC)C.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>CN(C=O)C.[Cu]I>[NH2:12][C:10](=[O:11])[CH2:9][C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=1[C:1]#[C:2][C:18]1[C:19]([C:20]([F:21])([F:22])[F:23])=[CH:14][N:15]=[C:16]([NH:24][C:25]2[CH:26]=[CH:27][C:28]([CH:31]3[CH2:36][CH2:35][CH2:34][CH2:33][N:32]3[C:37]([O:39][C:40]([CH3:43])([CH3:42])[CH3:41])=[O:38])=[CH:29][CH:30]=2)[N:17]=1

Participants

7

Reactant 4

HCID 8471TriethylamineHCID 11776TriphenylphosphineHCID 533429972-(2-Ethynylphenyl)acetamideHCID 86675715tert-Butyl 2-(4-((4-chloro-5-(trifluoromethyl)pyrimidin-2-yl)amino)phenyl)piperidine-1-carboxylate

Product 1

HCID 71229343tert-Butyl 2-(4-((4-((2-(2-amino-2-oxoethyl)phenyl)ethynyl)-5-(trifluoromethyl)pyrimidin-2-yl)amino)phenyl)piperidine-1-carboxylateYield 74%

Reagents, catalysts & solvents 2

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

Conditions

Temperature
120 °C

Procedure

To a nitrogen de-gassed solution of 2-(2-ethynylphenyl)acetamide (I39) (0.054 g, 0.788 mmol) and tert-butyl 2-(4-((4-chloro-5-(trifluoromethyl)pyrimidin-2-yl)amino)phenyl)piperidine-1-carboxylate (I37) in dry DMF (4 mL) were added triethylamine (0.159 mL, 1.138 mmol), triphenylphosphine (0.011 g, 0.043 mmol), trans-dichlorobis(triphenylphosphine) palladium(II) (0.020 g, 0.028 mmol) and CuI (0.008 g, 0.04 mmol). The reaction mixture was heated under microwave irradiation at 120° C. for 20 minutes. The reaction was concentrated to dryness in vacuo and purified by silica gel chromatography (Biotage Isolera, 40 g Si cartridge, 0-100% EtOAc in petroleum benzine 40-60° C., then 0-5% methanol in EtOAc) to give the title compound (I40) (0.122 g, 74% yield) as a yellow glassy solid; 1H NMR (400 MHz, d6-DMSO) δ 10.48 (s, 1H), 8.82 (s, 1H), 7.73 (d, J=8.7 Hz, 2H), 7.65-7.55 (m, 1H), 7.55-7.47 (m, 1H), 7.47-7.33 (m, 3H), 7.16 (d, J=8.5 Hz, 2H), 7.01 (s, 1H), 5.29-5.22 (m, 1H), 3.92 (d, J=13.1 Hz, 1H), 3.70 (s, 2H), 2.71 (t, J=13.3 Hz, 1H), 2.34-2.24 (m, 1H), 1.82-1.68 (m, 1H), 1.54 (d, J=11.3 Hz, 2H), 1.45-1.22 (m, 11H).

Workup

  1. concentrationThe reaction was concentrated to dryness in vacuo
  2. custompurified by silica gel chromatography (Biotage Isolera, 40 g Si cartridge, 0-100% EtOAc in petroleum benzine 40-60° C.

Sources & evidence

ORD record
ord-d91f80af56e242d7a804daca986065fa
Source dataset
uspto-grants-2015_04
Patent number
US09012461B2

Reaction notes

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