1,1'-Carbonyldiimidazole → 1-[5-(1-fluoromethyl-cyclopropyl)-2-p-tolyl-2H-pyrazol-3-yl]-3-{1-[1-(1-methyl-cyclopropanecarbonyl)-piperidin-4-yloxy]-isoquinolin-4-yl}-urea

Participants

Reaction Conditions

Reaction Steps

Add 5-(1-fluoromethyl-cyclopropyl)-2-p-tolyl-2H-pyrazol-3-ylamine (160.00 mg; 652.26 μmoles) dissolved in 1 L of DCM slowly to a solution of 1,1′-carbonyldiimidazole (158.65 mg, 978.39 μmoles) in DCM. Stir mixture at 40° C. for 7 hours. Then add a solution of [4-(4-Amino-isoquinolin-1-yloxy)-piperidin-1-yl]-(1-methyl-cyclopropyl)-methanone (Preparation 23, 212.25 mg, 652.26 μmoles, 1.00 equiv) in 1 mL of DCM. Stir mixture overnight. Evaporate solvent under N2. Purify first by HLB cartridge (6 g) using NH4CO3/MeOH (100:0 to 0:100) and then finally by HPLC (Kromasil C18 column (100×21.2 mm, 5 □m (Hi-Chrom). The mobile phase is water (solvent A) and acetonitrile (solvent B), both containing 0.05% trifluoroacetic acid (TFA). Gradient mode: 2 min at 40% of B, from 40 to 60% of B in 6 min. Finally, 2 min at 95% of B. Flow rate: 25 mL/min) affording 1-[5-(1-fluoromethyl-cyclopropyl)-2-p-tolyl-2H-pyrazol-3-yl]-3-{1-[1-(1-methyl-cyclopropanecarbonyl)-piperidin-4-yloxy]-isoquinolin-4-yl}-urea as a solid (19 mg, 5% yield). ES+ (m/z):597[M+1].

Provenance & Evidence