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

HRID 592362Notizen

Reaktionsgleichung

Reaktionsgleichung von HRID 592362
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[C:45]1([C:48]([O:50][CH3:51])=[O:49])[CH2:47][CH2:46]1)#[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>[CH3:51][O:50][C:48]([C:45]1([C:40]2[CH:41]=[CH:42][CH:43]=[CH:44][C:39]=2[C:37]#[C:38][C:2]2[C:7]([C:8]([F:11])([F:10])[F:9])=[CH:6][N:5]=[C:4]([NH:12][C:13]3[CH:18]=[CH:17][C:16]([CH:19]4[CH2:24][CH2:23][N:22]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH2:21][CH2:20]4)=[CH:15][CH:14]=3)[N:3]=2)[CH2:47][CH2:46]1)=[O:49]

Komponenten

8

Edukt 4

HCID 8471TriethylamineHCID 26255TetrafluoroborateHCID 86675716Tert-butyl 4-(4-((4-chloro-5-(trifluoromethyl)pyrimidin-2-yl)amino)phenyl)piperidine-1-carboxylateHCID 86712270Methyl 1-(2-ethynylphenyl)cyclopropanecarboxylate

Produkt 1

HCID 86712284tert-Butyl 4-(4-((4-((2-(1-(methoxycarbonyl)cyclopropyl)phenyl)ethynyl)-5-(trifluoromethyl)pyrimidin-2-yl)amino)phenyl)piperidine-1-carboxylateAusbeute 86,5 %

Reagenzien, Katalysatoren, Lösungsmittel 3

HCID 24350Copper(1+) iodide; Copper(I) iodide; Cuprous iodide; Cuprous iodide (CuI)KatalysatorHCID 178418476HCID 178418476, VerbindungKatalysatorHCID 6228DimethylformamideLösungsmittel

Reaktionsbedingungen

Temperatur
120 °C

Versuchsvorschrift

A solution of tert-butyl 4-(4-((4-chloro-5-(trifluoromethyl)pyrimidin-2-yl)amino)phenyl)piperidine-1-carboxylate (K3) (262 mg, 0.574 mmol), PdCl2(PPh3)2 (20 mg, 0.029 mmol,) t-Bu3PH.BF4 (8 mg, 0.03 mmol), CuI (5 mg, 0.03 mmol) and methyl 1-(2-ethynylphenyl)cyclopropanecarboxylate (K2) (138 mg, 0.689 mmol) in DMF (5.0 mL) was degassed with nitrogen for 10 minutes. Et3N (1.0 mL) was added and the resulting mixture heated under microwave irradiation for 20 minutes at 120° C. The resulting mixture was adsorbed onto silica gel and purified by column chromatography (Biotage Isolera, SiO2 cartridge, 0-40% EtOAc in petroleum benzine 40-60° C.) to give the title compound A3 as a yellow solid (308 mg, 86%); 1H NMR (400 MHz, d6-DMSO) δ 10.37 (s, 1H), 8.79 (s, 1H), 7.67 (d, J=8.2 Hz, 2H), 7.60 (dd, J=7.6, 1.0 Hz, 1H), 7.54-7.38 (m, 3H), 7.21 (d, J=8.6 Hz, 2H), 4.07 (d, J=11.6 Hz, 2H), 3.52 (s, 3H), 2.80 (s, 2H), 2.65 (J m, 1H), 1.74 (d, J=12.4 Hz, 2H), 1.64 (q, J=4.0 Hz, 2H), 1.49 (td, J=12.6, 4.1 Hz, 2H), 1.42 (s, 9H), 1.29 (q, J=4.2 Hz, 2H). LCMS-A: rt 7.083 min; m/z 619 [M−H]−.

Aufarbeitung

  1. custompurified by column chromatography (Biotage Isolera, SiO2 cartridge, 0-40% EtOAc in petroleum benzine 40-60° C.)

Quellen und Nachweise

ORD-Eintrag
ord-a81928cf3d93406ca36f10ad772403c2
Quelldatensatz
uspto-grants-2016_01
Patentnummer
US09238644B2

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