Water → HCID 67520782, compound

HRID 1926328Notes

Reaction equation

HRID 1926328 reaction equation
Br[C:2]1[CH:3]=[C:4]([C:9]2[O:10][C:11]3[CH:18]=[CH:17][CH:16]=[CH:15][C:12]=3[C:13]=2[Cl:14])[C:5]([NH2:8])=[N:6][CH:7]=1.[C:19]([O:23][C:24]([N:26]1[CH2:31][CH2:30][CH:29]([N:32]2[CH:36]=[C:35](B3OC(C)(C)C(C)(C)O3)[CH:34]=[N:33]2)[CH2:28][CH2:27]1)=[O:25])([CH3:22])([CH3:21])[CH3:20].O1CCOCC1.C([O-])([O-])=O.[Cs+].[Cs+].O>C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[Pd]>[C:19]([O:23][C:24]([N:26]1[CH2:27][CH2:28][CH:29]([N:32]2[CH:36]=[C:35]([C:2]3[CH:7]=[N:6][C:5]([NH2:8])=[C:4]([C:9]4[O:10][C:11]5[CH:18]=[CH:17][CH:16]=[CH:15][C:12]=5[C:13]=4[Cl:14])[CH:3]=3)[CH:34]=[N:33]2)[CH2:30][CH2:31]1)=[O:25])([CH3:22])([CH3:20])[CH3:21]

Participants

7

Reactant 5

HCID 962WaterHCID 10796Cesium carbonateHCID 312751,4-DioxaneHCID 45480279tert-butyl 4-[4-(tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl]piperidine-1-carboxylate2×HCID 67520824HCID 67520824, compound

Product 1

HCID 67520782HCID 67520782, compound

Reagents, catalysts & solvents 1

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

Conditions

Temperature
105 °C

Procedure

To a solution of 5-Bromo-3-(3-chlorobenzofuran-2-yl)-pyridin-2-ylamine (57.9 mg, 0.179 mmol) and 4-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-pyrazol-1-yl]-piperidine-1-carboxylic acid tert-butyl ester (69.5 mg, 0.184 mmol) in 1,4-dioxane (2.5 mL, 32 mmol) in a microwave reactor tube were added PS-PPh3-Pd (0.10 mmol/g loading; 100 mg, 0.0100 mmol; Argonaut) and a solution of Cs2CO3 (117 mg, 0.358 mmol) in H2O (0.75 mL, 42 mmol). The tube was sealed, evacuated and refilled with nitrogen (3×), and heated in the microwave reactor to 105° C. for 30 min. More 4-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-pyrazol-1-yl]-piperidine-1-carboxylic acid tert-butyl ester (21 mg, 0.056 mmol) was added, the tube was evacuated and refilled with nitrogen again (3×) and heated in the microwave reactor to 105° C. for 45 min. The resin was filtered off and washed with DCM. The combined filtrate and washings were diluted with DCM to ≈50 mL, washed with water and brine, dried over MgSO4, filtered, and concentrated in vacuo. The residue was chromatographed on silica gel [10 g/70 mL prepacked cartridge, eluting with DCM→1% MeOH in DCM→2% MeOH in DCM]. Fractions containing product were combined and dried in vacuo. One obtained the title compound as a yellow solid. 1H NMR (400 MHz, CDCl3): δ=8.30 (d, J=2.4 Hz, 1H), 8.09 (d, J=2.4 Hz, 1), 7.74 (s, 1H), 7.65 (dd, J=7.2, 1.2 Hz, 1H), 7.63 (s, 1H), 7.52 (dd, J=7.0, 1.4 Hz, 1H), 7.41 (ddd, J=1.6, 7.2, 7.2 Hz, 1H), 7.38 (ddd, J=1.4, 7.0, 7.0 Hz, 1H), 5.27 (brs, 2H), 4.37-4.17 (m, 3H), 2.91 (brt, J=11.2 Hz, 2H), 2.18 (brdd, J=2.2, 12.8 Hz, 2H), 1.97 (dq, J=12.4, 4.0 Hz, 2H), 1.48 (s, 9H). MS(ES+): m/z=494.15/496.08 (100/48) [MH+]. HPLC: tR=3.23 min (nonpolar—5 min, ZQ3).

Workup

  1. customThe tube was sealed
  2. customevacuated
  3. additionrefilled with nitrogen (3×)
  4. customthe tube was evacuated
  5. additionrefilled with nitrogen again (3×)
  6. temperatureheated in the microwave reactor to 105° C. for 45 min
  7. filtrationThe resin was filtered off
  8. washwashed with DCM
  9. additionThe combined filtrate and washings were diluted with DCM to ≈50 mL
  10. washwashed with water and brine
  11. dry with materialdried over MgSO4
  12. filtrationfiltered
  13. concentrationconcentrated in vacuo
  14. customThe residue was chromatographed on silica gel [10 g/70 mL prepacked cartridge, eluting with DCM→1% MeOH in DCM→2% MeOH in DCM]
  15. additionFractions containing product
  16. customdried in vacuo

Sources & evidence

ORD record
ord-7aaef0e6f93d45a387f5dbdc35c21c19
Source dataset
uspto-grants-2012_05
Patent number
US08178668B2

Reaction notes

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