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

HRID 592359Notes

Reaction equation

HRID 592359 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:18]=[CH:17][C:16]([CH:19]3[CH2:24][CH2:23][N:22]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH2:21][CH2:20]3)=[CH:15][CH:14]=2)[N:3]=1.F[B-](F)(F)F.[C:37]([C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][C:40]=1[CH:45]([CH2:49][CH3:50])[C:46]([NH2:48])=[O:47])#[CH:38].CCN(CC)CC>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>[NH2:48][C:46](=[O:47])[CH:45]([C:40]1[CH:41]=[CH:42][CH:43]=[CH:44][C:39]=1[C:37]#[C:38][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:18]=[CH:17][C:16]([CH:19]3[CH2:24][CH2:23][N:22]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH2:21][CH2:20]3)=[CH:15][CH:14]=2)[N:3]=1)[CH2:49][CH3:50]

Participants

8

Reactant 4

HCID 8471TriethylamineHCID 26255TetrafluoroborateHCID 86675716Tert-butyl 4-(4-((4-chloro-5-(trifluoromethyl)pyrimidin-2-yl)amino)phenyl)piperidine-1-carboxylateHCID 867122692-(2-Ethynylphenyl)butanamide

Product 1

HCID 86712282tert-Butyl 4-(4-((4-((2-(1-amino-1-oxobutan-2-yl)phenyl)ethynyl)-5-(trifluoromethyl)pyrimidin-2-yl)amino)phenyl)piperidine-1-carboxylateYield 68.2%

Reagents, catalysts & solvents 3

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

Conditions

Temperature
120 °C

Procedure

A mixture of tert-butyl 4-(4-((4-chloro-5-(trifluoromethyl)pyrimidin-2-yl)amino)phenyl)piperidine-1-carboxylate (K3) (193 mg, 0.422 mmol), PdCl2(PPh3)2 (15 mg, 0.021 mmol), t-Bu3PH.BF4 (6 mg, 0.021 mmol), CuI (4 mg, 0.021 mmol) and 2-(2-ethynylphenyl)butanamide (K1) (87 mg, 0.47 mmol) in DMF (3.0 mL) was degassed with nitrogen for 10 minutes. Et3N (1.0 mL) was added and the resulting mixture was heated under microwave irradiation at 120° C. for 20 minutes. The volatiles were removed under reduced pressure and the residue was adsorbed onto silica gel then purified by column chromatography (Biotage Isolera, SiO2 cartridge, 0-100% EtOAc in petroleum benzine 40-60° C.) to give the title compound A1 as a yellow solid (175 mg, 68%); 1H NMR (400 MHz, d6-DMSO) δ 10.39 (s, 1H), 8.88-8.76 (m, 1H), 7.67 (d, J=8.5 Hz, 2H), 7.63-7.47 (m, 3H), 7.37 (td, J=7.4, 1.6 Hz, 1H), 7.27-7.17 (m, 3H), 7.01 (s, 1H), 4.07 (s, 2H), 3.89 (dd, J=8.6, 6.4 Hz, 1H), 2.80 (br, 2H), 2.64 (J m, 1H), 1.98-1.90 (m, 1H), 1.74 (d, J=12.7 Hz, 2H), 1.70-1.60 (m, 1H), 1.55-1.44 (m, 2H), 1.42 (s, 9H), 0.87 (t, J=7.3 Hz, 3H). LCMS-A: rt 6.726 min; m/z 606 [M−H]−.

Workup

  1. customThe volatiles were removed under reduced pressure
  2. customthen purified by column chromatography (Biotage Isolera, SiO2 cartridge, 0-100% EtOAc in petroleum benzine 40-60° C.)

Sources & evidence

ORD record
ord-3e2efca6b1644a8b86c5c372d46224bc
Source dataset
uspto-grants-2016_01
Patent number
US09238644B2

Reaction notes

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