Triethylamine → tert-Butyl 4-(4-((4-((3-oxoisoindolin-4-yl)ethynyl)-5-(trifluoromethyl)pyrimidin-2-yl)amino)phenyl)piperazine-1-carboxylate

HRID 1485195Notes

Reaction equation

HRID 1485195 reaction equation
[C:1]([C:3]1[CH:4]=[CH:5][CH:6]=[C:7]2[C:11]=1[C:10](=[O:12])[NH:9][CH2:8]2)#[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]([N:31]3[CH2:36][CH2:35][N:34]([C:37]([O:39][C:40]([CH3:43])([CH3:42])[CH3:41])=[O:38])[CH2:33][CH2:32]3)=[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.CCOC(C)=O.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.CO>[O:12]=[C:10]1[C:11]2[C:7](=[CH:6][CH:5]=[CH:4][C:3]=2[C:1]#[C:2][C:18]2[C:19]([C:20]([F:22])([F:21])[F:23])=[CH:14][N:15]=[C:16]([NH:24][C:25]3[CH:26]=[CH:27][C:28]([N:31]4[CH2:32][CH2:33][N:34]([C:37]([O:39][C:40]([CH3:43])([CH3:42])[CH3:41])=[O:38])[CH2:35][CH2:36]4)=[CH:29][CH:30]=3)[N:17]=2)[CH2:8][NH:9]1

Participants

10

Reactant 4

HCID 8471TriethylamineHCID 11776TriphenylphosphineHCID 86675713Tert-butyl 4-(4-((4-chloro-5-(trifluoromethyl)pyrimidin-2-yl)amino)phenyl)piperazine-1-carboxylateHCID 866757197-Ethynylisoindolin-1-one

Product 1

HCID 86675721tert-Butyl 4-(4-((4-((3-oxoisoindolin-4-yl)ethynyl)-5-(trifluoromethyl)pyrimidin-2-yl)amino)phenyl)piperazine-1-carboxylateYield 66.4%

Reagents, catalysts & solvents 5

HCID 24350Copper(1+) iodide; Copper(I) iodide; Cuprous iodide; Cuprous iodide (CuI)CatalystHCID 178418476HCID 178418476, compoundCatalystHCID 887MethanolSolventHCID 6228DimethylformamideSolventHCID 8857Ethyl AcetateSolvent

Conditions

Temperature
120 °C

Procedure

To a nitrogen de-gassed solution of 7-ethynylisoindolin-1-one (161) (0.074 g, 0.47 mmol) and tert-butyl 4-(4-((4-chloro-5-(trifluoromethyl)pyrimidin-2-yl)amino)phenyl)piperazine-1-carboxylate (I3) (0.180 g, 0.393 mmol), in dry DMF (7 mL) were added triethylamine (0.219 mL, 1.57 mmol) followed by triphenylphosphine (0.015 g, 0.059 mmol), trans-dichlorobis(triphenylphosphine)palladium(II) (0.028 g, 0.039 mmol) and CuI (0.011 g, 0.059 mmol). The reaction mixture was heated under microwave irradiation at 120° C. for 20 minutes and then 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 (I62) (0.151 g, 66% yield) as an orange gum; 1H NMR (400 MHz, d6-DMSO) δ 10.32 (s, 1H), 8.77 (s, 1H), 8.72 (s, 1H), 7.75-7.67 (m, 2H), 7.67-7.64 (m, 1H), 7.60-7.56 (m, 2H).), 6.95 (d, J=9.1 Hz, 2H), 4.40 (s, 2H), 3.51-3.42 (m, 4H), 3.11-3.00 (m, 4H), 1.42 (s, 9H). LCMS Method C: rt 6.23 min, m/z 579.2 [M+H]+.

Workup

  1. concentrationconcentrated 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-3757f535234c440e9a3ace9c672cc173
Source dataset
uspto-grants-2016_08
Patent number
US09421205B2

Reaction notes

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