Water → HCID 67521024, Verbindung

HRID 1926241Notizen

Reaktionsgleichung

Reaktionsgleichung von HRID 1926241
[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([N:14]2[CH:18]=[C:17]([C:19]3[CH:20]=[N:21][C:22]([NH2:34])=[C:23](B4OC(C)(C)C(C)(C)O4)[CH:24]=3)[CH:16]=[N:15]2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:35][C:36]1[CH:37]=[CH:38][CH:39]=[C:40]2[C:45]=1[CH:44]=[N:43][C:42](OS(C(F)(F)F)(=O)=O)=[CH:41]2.O1CCOCC1.C([O-])([O-])=O.[Cs+].[Cs+].O>C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[Pd]>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][CH:11]([N:14]2[CH:18]=[C:17]([C:19]3[CH:20]=[N:21][C:22]([NH2:34])=[C:23]([C:42]4[N:43]=[CH:44][C:45]5[C:40]([CH:41]=4)=[CH:39][CH:38]=[CH:37][C:36]=5[CH3:35])[CH:24]=3)[CH:16]=[N:15]2)[CH2:12][CH2:13]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]

Komponenten

7

Edukt 5

HCID 962WaterHCID 10796Cesium carbonateHCID 312751,4-DioxaneHCID 534879604-[4-[6-Amino-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)pyridin-3-yl]pyrazol-1-yl]piperidine-1-carboxylic acid tert-butyl esterHCID 86633135HCID 86633135, Verbindung

Produkt 1

HCID 67521024HCID 67521024, Verbindung

Reagenzien, Katalysatoren, Lösungsmittel 1

HCID 15220664Palladium--triphenylphosphane (1/1)Katalysator

Reaktionsbedingungen

Temperatur
105 °C

Versuchsvorschrift

To a solution of 4-{4-[6-amino-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyridin-3-yl]-pyrazol-1-yl}-piperidine-1-carboxylic acid tert-butyl ester (BB3) (18.9 mg, 0.0403 mmol), trifluoromethanesulfonic acid 8-methylisoquinolin-3-yl ester (12.0 mg, 0.0412 mmol), and PS-PPh3-Pd (0.10 mmol/g loading; 26 mg, 0.0026 mmol; Argonaut) in 1,4-dioxane (0.70 mL, 9.0 mmol) in a sealable microwave tube was added a solution of Cs2CO3 (26.7 mg, 0.0819 mmol) in H2O (0.20 mL, 11 mmol). The tube was sealed, evacuated and refilled with nitrogen (3×), and heated in the microwave reactor to 105° C. for 30 minutes. The resin was filtered off and washed with DCM. The combined filtrate and washings were washed with water and brine, dried over MgSO4, filtered, and concentrated in vacuo. The residue was purified by preparative TLC [20×20 cm plate, 500 μm layer of silica gel, eluting with 3% MeOH in DCM (2×) and 4% MeOH in DCM (2×)]. Material from the main band was collected and dried in vacuo overnight giving the title compound as a yellow glassy solid. 1H NMR (400 MHz, CDCl3): δ=9.50 (s, 1H), 8.26 (d, J=2.0 Hz, 1H), 8.02 (d, J=0.4 Hz, 1H), 7.97 (d, J=2.4 Hz, 1H), 7.78 (d, J=0.8 Hz, 1H), 7.75 (d, J=8.4 Hz, 1H), 7.67 (d, J=0.4 Hz, 1H), 7.62 (dd, J=7.2, 8.4 Hz, 1H), 7.42 (dt, J=7.2, 0.8 Hz, 1H), 6.56 (brs, 2H), 4.38-4.19 (m, 3H), 2.92 (brs, J=11.0 Hz, 2H), 2.83 (s, 3H), 2.19 (brdd, J=2.2, 11.4 Hz, 2H), 1.95 (dq, J=4.0, 12.0 Hz, 2H), 1.49 (s, 9H). MS(ES+): m/z=485.23 (100) [MH+], 429.16 (7) [MH+-isobutene]. HPLC: tR=2.88 min (polar—5 min, ZQ3).

Aufarbeitung

  1. customThe tube was sealed
  2. customevacuated
  3. additionrefilled with nitrogen (3×)
  4. filtrationThe resin was filtered off
  5. washwashed with DCM
  6. washThe combined filtrate and washings were washed with water and brine
  7. dry with materialdried over MgSO4
  8. filtrationfiltered
  9. concentrationconcentrated in vacuo
  10. customThe residue was purified by preparative TLC [20×20 cm plate, 500 μm layer of silica gel, eluting with 3% MeOH in DCM (2×) and 4% MeOH in DCM (2×)]
  11. customMaterial from the main band was collected
  12. customdried in vacuo overnight

Quellen und Nachweise

ORD-Eintrag
ord-c86a5faa535c4814b4872751443f9288
Quelldatensatz
uspto-grants-2012_05
Patentnummer
US08178668B2

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