Dichloromethane → Diethyl (4-{[4-({7-[1-(2-methoxyethyl)-1H-pyrazol-4-yl]-2-methyl-3-oxo-2,3-dihydro-1H-isoindol-4-yl}amino)-5-(trifluoromethyl)pyrimidin-2-yl]amino}benzyl)phosphonate

HRID 511270

Reaktionsgleichung

Reaktionsgleichung von HRID 511270
Br[C:2]1[CH:3]=[CH:4][C:5]([NH:13][C:14]2[C:19]([C:20]([F:23])([F:22])[F:21])=[CH:18][N:17]=[C:16]([NH:24][C:25]3[CH:39]=[CH:38][C:28]([CH2:29][P:30](=[O:37])([O:34][CH2:35][CH3:36])[O:31][CH2:32][CH3:33])=[CH:27][CH:26]=3)[N:15]=2)=[C:6]2[C:10]=1[CH2:9][N:8]([CH3:11])[C:7]2=[O:12].[CH3:40][O:41][CH2:42][CH2:43][N:44]1[CH:48]=[C:47](B2OC(C)(C)C(C)(C)O2)[CH:46]=[N:45]1.C(=O)([O-])[O-].[K+].[K+].ClCCl>C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].O.O1CCOCC1>[CH3:40][O:41][CH2:42][CH2:43][N:44]1[CH:48]=[C:47]([C:2]2[CH:3]=[CH:4][C:5]([NH:13][C:14]3[C:19]([C:20]([F:21])([F:22])[F:23])=[CH:18][N:17]=[C:16]([NH:24][C:25]4[CH:39]=[CH:38][C:28]([CH2:29][P:30](=[O:37])([O:34][CH2:35][CH3:36])[O:31][CH2:32][CH3:33])=[CH:27][CH:26]=4)[N:15]=3)=[C:6]3[C:10]=2[CH2:9][N:8]([CH3:11])[C:7]3=[O:12])[CH:46]=[N:45]1

Komponenten

8

Edukt 4

HCID 6344DichloromethaneHCID 11430Potassium CarbonateHCID 112304911-(2-Methoxyethyl)-1H-pyrazole-4-boronic acid, pinacol esterHCID 58292897Diethyl [4-({4-[(7-bromo-2-methyl-3-oxo-2,3-dihydro-1H-isoindol-4-yl)amino]-5(trifluoromethyl)pyrimidin-2-yl}amino)benzyl]phosphonate

Produkt 1

HCID 58293052Diethyl (4-{[4-({7-[1-(2-methoxyethyl)-1H-pyrazol-4-yl]-2-methyl-3-oxo-2,3-dihydro-1H-isoindol-4-yl}amino)-5-(trifluoromethyl)pyrimidin-2-yl]amino}benzyl)phosphonateAusbeute 19,6 %

Reagenzien, Katalysatoren, Lösungsmittel 3

HCID 178418228Bis(cyclopenta-1,4-dien-1-yl(diphenyl)phosphane);dichloropalladium;iron(2+)KatalysatorHCID 962WaterLösungsmittelHCID 312751,4-DioxaneLösungsmittel

Versuchsvorschrift

A mixture of diethyl [4-({4-[(7-bromo-2-methyl-3-oxo-2,3-dihydro-1H-isoindol-4-yl)amino]-5-(trifluoromethyl)pyrimidin-2-yl}amino)benzyl]phosphonate (10.0 mg, 0.0159 mmol), 1-(2-methoxyethyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (8.02 mg, 0.0318 mmol), potassium carbonate (6.60 mg, 0.0477 mmol), 1,4-dioxane (0.4 mL), H2O (0.1 mL) and [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II), complex with dichloromethane (1:1) (1.30 mg, 0.00159 mmol) was evacuated and purged with N2. The mixture was irradiated in a microwave reactor at 100° C. for 30 minutes. The crude mixture was passed through a Thiol-SPE column to remove Pd and purified by MDP to obtain the title compound (2.1 mg, 19.6% yield). 1H NMR (400 MHz, CD3OD) δ=1.25 (t, J=7.1 Hz, 6 H), 3.21 (s, 3 H), 3.30 (d, J=22.7 Hz), 3.35 (s, 3 H), 3.79 (t, J=5.2 Hz, 2 H), 4.01-4.13 (m, 4 H), 4.37 (t, J=5.2 Hz, 2 H), 4.60 (s, 2 H), 7.37 (dd, J=8.6, 2.3 Hz, 2 H), 7.57 (d, J=8.6 Hz, 2 H), 7.72 (d, J=8.8 Hz, 1 H), 7.94 (s, 1 H), 8.08 (s, 1 H), 8.36 (s, 1 H), 8.68 (br. s., 1 H). MS (ES+): m/z 674.34 (100) [MH+]; HPLC: tR=1.05 min (UPLC, purity).

Aufarbeitung

  1. customwas evacuated
  2. custompurged with N2
  3. customThe mixture was irradiated in a microwave reactor at 100° C. for 30 minutes
  4. customto remove Pd
  5. custompurified by MDP

Quellen und Nachweise

ORD-Eintrag
ord-57cb16b31eaa40b39a8398d2228ae705
Quelldatensatz
uspto-grants-2015_08
Patentnummer
US09096624B2

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