Water → HCID 67520796, compound

HRID 1926233Notes

Reaction equation

HRID 1926233 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].[Cl: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.C([O-])([O-])=O.[Cs+].[Cs+].O>O1CCOCC1.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>[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:42]4[N:43]=[CH:44][C:45]5[C:40]([CH:41]=4)=[CH:39][CH:38]=[CH:37][C:36]=5[Cl:35])[CH:24]=3)[CH:16]=[N:15]2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]

Participants

7

Reactant 4

HCID 962WaterHCID 10796Cesium carbonateHCID 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 56926517HCID 56926517, compound

Product 1

HCID 67520796HCID 67520796, compound

Reagents, catalysts & solvents 2

HCID 178418397HCID 178418397, compoundCatalystHCID 312751,4-DioxaneSolvent

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) (70.1 mg, 0.149 mmol), trifluoromethanesulfonic acid 8-chloroisoquinolin-3-yl ester (47.9 mg, 0.154 mmol), and Pd(PPh3)4 (11.5 mg, 0.00995 mmol) in 1,4-dioxane (2.3 mL, 29 mmol in a sealable microwave tube was added a solution of Cs2CO3 (95.5 mg, 0.293 mmol) in H2O (0.65 mL, 36 mmol). The tube was sealed, evacuated and refilled with nitrogen (3×), and heated in the microwave reactor to 105° C. for 30 minutes. The reaction mixture was diluted with DCM, washed with water, sat. NaHCO3 solution, and brine, dried over MgSO4, filtered, and concentrated in vacuo. The crude material was chromatographed on silica gel [20 g/70 mL prepacked cartridge, eluting with DCM→1% MeOH in DCM→2% MeOH in DCM→3% MeOH in DCM]. Fractions containing the title compound were combined and dried in vacuo, yielding the title compound as a glassy, yellow solid. 1H NMR (400 MHz, CDCl3): δ=9.70 (t, J=0.8 Hz, 1H), 8.29 (d, J=2.0 Hz, 1H), 8.04 (d, J=0.4 Hz, 1H), 7.96 (d, J=2.4 Hz, 1H), 7.82 (dt, J=5.8, 3.0 Hz, 1H), 7.78 (d, J=1.2 Hz, 1H), 7.67 (d, J=0.8 Hz, 1H), 7.66-7.62 (m, 2H), 6.47 (brs, 2H), 4.40-4.19 (m, 3H), 2.92 (brt, J=11.6 Hz, 2H), 2.19 (brdd, J=12.2 Hz, 2H), 1.95 (dq, J=4.0, 12.0 Hz, 2H), 1.49 (s, 9H). MS(ES+): m/z=505.16/507.13 (100/42) [MH+], 449.05/451.07 (3/1) [MH+-isobutene]. HPLC: tR=3.15 min (polar—5 min, ZQ3).

Workup

  1. customThe tube was sealed
  2. customevacuated
  3. additionrefilled with nitrogen (3×)
  4. additionThe reaction mixture was diluted with DCM
  5. washwashed with water, sat. NaHCO3 solution, and brine
  6. dry with materialdried over MgSO4
  7. filtrationfiltered
  8. concentrationconcentrated in vacuo
  9. customThe crude material was chromatographed on silica gel [20 g/70 mL prepacked cartridge, eluting with DCM→1% MeOH in DCM→2% MeOH in DCM→3% MeOH in DCM]
  10. additionFractions containing the title compound
  11. customdried in vacuo

Sources & evidence

ORD record
ord-304404e912c94d18adf564b8d1f0cdba
Source dataset
uspto-grants-2012_05
Patent number
US08178668B2

Reaction notes

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