Potassium Carbonate → 3-(5-Chloro-8-fluoroisoquinolin-3-yl)-5-[1-(8-methyl-8-azabicyclo [3.2.1]-oct-3-yl)-1H-pyrazol-4-yl]-pyridin-2-ylamine

HRID 1926317Notizen

Reaktionsgleichung

Reaktionsgleichung von HRID 1926317
I[C:2]1[CH:3]=[N:4][N:5]([CH:7]2[CH2:13][CH:12]3[N:14]([CH3:15])[CH:9]([CH2:10][CH2:11]3)[CH2:8]2)[CH:6]=1.[Cl:16][C:17]1[CH:26]=[CH:25][C:24]([F:27])=[C:23]2[C:18]=1[CH:19]=[C:20]([C:28]1[C:29]([NH2:43])=[N:30][CH:31]=[C:32](B3OC(C)(C)C(C)(C)O3)[CH:33]=1)[N:21]=[CH:22]2.C(=O)([O-])[O-].[K+].[K+]>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.COCCOC.O>[Cl:16][C:17]1[CH:26]=[CH:25][C:24]([F:27])=[C:23]2[C:18]=1[CH:19]=[C:20]([C:28]1[C:29]([NH2:43])=[N:30][CH:31]=[C:32]([C:2]3[CH:3]=[N:4][N:5]([CH:7]4[CH2:13][CH:12]5[N:14]([CH3:15])[CH:9]([CH2:10][CH2:11]5)[CH2:8]4)[CH:6]=3)[CH:33]=1)[N:21]=[CH:22]2

Komponenten

6

Edukt 3

HCID 11430Potassium CarbonateHCID 67520645HCID 67520645, VerbindungHCID 675208023-(4-Iodopyrazol-1-yl)-8-methyl-8-azabicyclo[3.2.1]octane

Produkt 1

HCID 675208353-(5-Chloro-8-fluoroisoquinolin-3-yl)-5-[1-(8-methyl-8-azabicyclo [3.2.1]-oct-3-yl)-1H-pyrazol-4-yl]-pyridin-2-ylamine

Reagenzien, Katalysatoren, Lösungsmittel 2

HCID 178418397HCID 178418397, VerbindungKatalysatorHCID 18180031Water 1,2-dimethoxyethaneLösungsmittel

Reaktionsbedingungen

Temperatur
100 °C

Versuchsvorschrift

A solution of 3-(4-iodopyrazol-1-yl)-8-methyl-8-azabicyclo[3.2.1]octane (42.7 mg, 0.135 mmol), 3-(5-chloro-8-fluoroisoquinolin-3-yl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-pyridin-2-ylamine (0.070 g, 0.18 mmol), potassium carbonate (55.9 mg, 0.404 mmol), and Pd(PPh3)4 (9 mg, 0.008 mmol) in previously degassed DME/Water (4:1) (3.0 mL) was placed in a microwave tube and evacuated and charged with N2 (2×). The reaction mixture was heated in the microwave reactor to 100° C. for 45 min. The reaction mixture was diluted with EtOAc and washed with H2O (2×), brine (2×), dried over Na2SO4, filtered and concentrated in vacuo. The crude material was purified by chromatography on silica gel [eluting with 10% MeOH in CHCl3], passing through an SCX cartridge, and finally by the MDP. The fractions containing product were combined, concentrated in vacuo, and partitioned between CHCl3 and sat. NaHCO3. The organic phase was dried over Na2SO4, filtered and concentrated in vacuo resulting in the title compound as a yellow solid. 1H NMR (400 MHz, DMSO-d6): δ=1.64-1.72 (m, 2H), 1.77-1.86 (m, 2H), 1.97-2.06 (m, 2H), 2.07-2.17 (m, 2H), 2.26 (s, 3H), 3.20 (br. s., 2H), 4.47 (tt, J=11.7, 5.9 Hz, 1H), 6.89 (br. s., 2H), 7.54 (dd, J=9.9, 8.4 Hz, 1H), 7.87 (s, 1H), 8.03 (dd, J=8.4, 4.8 Hz, 1H), 8.15 (d, J=2.2 Hz, 1H), 8.25 (s, 1H), 8.35 (d, J=2.2 Hz, 1H), 8.37 (s, 1H), 9.64 (s, 1H). MS (ES+): m/z=463.13/465.15 (76/24) [MH+]. HPLC: tR=1.88 min (ZQ2, polar—5 min).

Aufarbeitung

  1. customevacuated
  2. additioncharged with N2 (2×)
  3. additionThe reaction mixture was diluted with EtOAc
  4. washwashed with H2O (2×), brine (2×)
  5. dry with materialdried over Na2SO4
  6. filtrationfiltered
  7. concentrationconcentrated in vacuo
  8. customThe crude material was purified by chromatography on silica gel [eluting with 10% MeOH in CHCl3]
  9. additionThe fractions containing product
  10. concentrationconcentrated in vacuo
  11. custompartitioned between CHCl3 and sat. NaHCO3
  12. dry with materialThe organic phase was dried over Na2SO4
  13. filtrationfiltered
  14. concentrationconcentrated in vacuo

Quellen und Nachweise

ORD-Eintrag
ord-22ea78aa730147cea6a86526de8ee42d
Quelldatensatz
uspto-grants-2012_05
Patentnummer
US08178668B2

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