Potassium Phosphate, Tribasic → N-((1R,3S)-3-(5-fluoro-2-(5-fluoro-1-tosyl-1H-pyrrolo[2,3-b]pyridin-3-yl)pyrimidin-4-ylamino)cyclohexyl)pyrrolidine-1-carboxamide

HRID 527072

Reaktionsgleichung

Reaktionsgleichung von HRID 527072
Cl[C:2]1[N:7]=[C:6]([NH:8][C@H:9]2[CH2:14][CH2:13][CH2:12][C@@H:11]([NH:15][C:16]([N:18]3[CH2:22][CH2:21][CH2:20][CH2:19]3)=[O:17])[CH2:10]2)[C:5]([F:23])=[CH:4][N:3]=1.[F:24][C:25]1[CH:26]=[C:27]2[C:33](B3OC(C)(C)C(C)(C)O3)=[CH:32][N:31]([S:43]([C:46]3[CH:51]=[CH:50][C:49]([CH3:52])=[CH:48][CH:47]=3)(=[O:45])=[O:44])[C:28]2=[N:29][CH:30]=1.[O-]P([O-])([O-])=O.[K+].[K+].[K+].C1(P(C2CCCCC2)C2C=CC=CC=2C2C(C(C)C)=CC(C(C)C)=CC=2C(C)C)CCCCC1>O.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[F:23][C:5]1[C:6]([NH:8][C@H:9]2[CH2:14][CH2:13][CH2:12][C@@H:11]([NH:15][C:16]([N:18]3[CH2:22][CH2:21][CH2:20][CH2:19]3)=[O:17])[CH2:10]2)=[N:7][C:2]([C:33]2[C:27]3[C:28](=[N:29][CH:30]=[C:25]([F:24])[CH:26]=3)[N:31]([S:43]([C:46]3[CH:51]=[CH:50][C:49]([CH3:52])=[CH:48][CH:47]=3)(=[O:44])=[O:45])[CH:32]=2)=[N:3][CH:4]=1

Komponenten

7

Edukt 4

HCID 62657Potassium Phosphate, TribasicHCID 111557942-Dicyclohexylphosphino-2',4',6'-triisoprophylbiphenylHCID 672856905-fluoro-1-((4-methylphenyl)sulfonyl)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrrolo(2,3-b)pyridineHCID 86667450N-((1R,3S)-3-((2-Chloro-5-fluoropyrimidin-4-yl)amino)cyclohexyl)pyrrolidine-1-carboxamide2×

Produkt 1

HCID 68008350N-((1R,3S)-3-(5-fluoro-2-(5-fluoro-1-tosyl-1H-pyrrolo[2,3-b]pyridin-3-yl)pyrimidin-4-ylamino)cyclohexyl)pyrrolidine-1-carboxamide

Reagenzien, Katalysatoren, Lösungsmittel 2

HCID 9811564Bis(dibenzylideneacetone)palladiumKatalysatorHCID 962WaterLösungsmittel

Reaktionsbedingungen

Temperatur
125 °C

Versuchsvorschrift

A solution of N-((1R,3S)-3-(2-chloro-5-fluoropyrimidin-4-ylamino)cyclohexyl)-pyrrolidine-1-carboxamide, 67e, (6.8 g, 20.0 mmol), 5-fluoro-1-(p-tolylsulfonyl)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrrolo[2,3-b]pyridine, 44a, (12.5 g, 30.0 mmol) and K3PO4 (17.0 g, 80.0 mmol) in 2-methyl THF (180 mL) and water (20 mL) was degassed under nitrogen for 30 min. To the mixture was added dicyclohexyl-[2-(2,4,6-triisopropylphenyl)phenyl]phosphane (XPhos) (1.1 g, 2.4 mmol) and Pd2(dba)3 (0.5 g, 0.5 mmol). The reaction mixture was heated in a pressure bottle at 125° C. for 2.5 hr. The reaction mixture was filtered through celite, the solvent was removed under reduced pressure. The resulting residue was purified by silica gel chromatography (8% MeOH/CH2Cl2) to afford 11.5 g of the desired product: 1H NMR (300 MHz, CDCl3) δ 8.54 (s, 1H), 8.49 (dd, J=9.0, 2.8 Hz, 1H), 8.32 (d, J=2.1 Hz, 1H), 8.13 (d, J=8.3 Hz, 2H), 8.07 (d, J=3.2 Hz, 1H), 7.30 (d, J=8.5 Hz, 2H), 4.98 (d, J=6.3 Hz, 1H), 4.37-4.16 (m, 1H), 4.08 (d, J=7.3 Hz, 1H), 3.99-3.80 (m, 1H), 3.33 (t, J=6.5 Hz, 4H), 2.52 (d, J=11.6 Hz, 1H), 2.39 (s, 3H), 2.29 (d, J==11.3 Hz, 1H), 2.12 (d, J=11.1 Hz, 1H), 1.99-1.81 (m, 5H), 1.70-1.55 (m, 1H), 1.22-1.08 (m, 2H).

Aufarbeitung

  1. filtrationThe reaction mixture was filtered through celite
  2. customthe solvent was removed under reduced pressure
  3. customThe resulting residue was purified by silica gel chromatography (8% MeOH/CH2Cl2)

Quellen und Nachweise

ORD-Eintrag
ord-e9d5562951864cf1b46dec4cfc133ad1
Quelldatensatz
uspto-grants-2016_05
Patentnummer
US09345708B2

Verknüpfte Notizen

Wird geladen…