Water → 4-{4-[6-Amino-5-(4-fluoroisoquinolin-3-yl)-pyridin-3-yl]-pyrazol-1-yl}-piperidine-1-carboxylic acid tert-butyl ester

HRID 1926252Notes

Reaction equation

HRID 1926252 reaction equation
[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].[F:35][C:36]1[C:45]2[C:40](=[CH:41][CH:42]=[CH:43][CH:44]=2)[CH:39]=[N:38][C:37]=1OS(C(F)(F)F)(=O)=O.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[CH2:13][CH2:12][CH:11]([N:14]2[CH:18]=[C:17]([C:19]3[CH:20]=[N:21][C:22]([NH2:34])=[C:23]([C:37]4[N:38]=[CH:39][C:40]5[C:45]([C:36]=4[F:35])=[CH:44][CH:43]=[CH:42][CH:41]=5)[CH:24]=3)[CH:16]=[N:15]2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]

Participants

7

Reactant 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 86633138Trifluoromethanesulfonic acid 4-fluoroisoquinolin-3-yl ester

Product 1

HCID 675203744-{4-[6-Amino-5-(4-fluoroisoquinolin-3-yl)-pyridin-3-yl]-pyrazol-1-yl}-piperidine-1-carboxylic acid tert-butyl ester

Reagents, catalysts & solvents 1

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

Conditions

Temperature
105 °C

Procedure

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) (39.0 mg, 0.0831 mmol), trifluoromethanesulfonic acid 4-fluoroisoquinolin-3-yl ester (25.1 mg, 0.0850 mmol), and PS-PPh3-Pd (0.10 mmol/g loading; 55 mg, 0.0055 mmol; Argonaut) in 1,4-dioxane (1.3 mL, 16 mmol) in a sealable microwave tube was added a solution of Cs2CO3 (53.1 mg, 0.163 mmol) in H2O (0.36 mL, 20 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 3.5% MeOH in DCM (3×)]. 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=9.14 (s, 1H), 8.29 (d, J=2.2 Hz, 1H), 8.18 (dd, J=0.8, 8.2 Hz, 1H), 8.06 (dt, J=8.0, 0.8 Hz, 1H), 8.01 (dd, J=2.6, 2.6 Hz, 1H), 7.84 (ddd, J=1.2, 7.2, 8.2 Hz, 1H), 7.75 (d, J=0.6 Hz, 1H), 7.72 (ddd, J=1.0, 7.0, 8.2 Hz, 1H), 7.64 (d, J=0.6 Hz, 1H), 5.90 (brs, 2H), 4.40-4.15 (m, 3H), 2.91 (brt, J=10.6 Hz, 2H), 2.18 (brdd, J=2.2, 12.4 Hz, 2H), 1.97 (dq, J=4.4, 12.2 Hz, 2H), 1.48 (s, 9H). MS(ES+): m/z=489.16 (100) [MH+], 433.16 (4) [MH+-isobutene]. HPLC: tR=3.05 min (polar—5 min, ZQ3), 2.71 min (polar—5 min, ZQ2).

Workup

  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 3.5% MeOH in DCM (3×)]
  11. customMaterial from the main band was collected
  12. customdried in vacuo overnight

Sources & evidence

ORD record
ord-c9c6b9e726ef4e5793d828b0c9787c74
Source dataset
uspto-grants-2012_05
Patent number
US08178668B2

Reaction notes

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